IL SONNO VISTO DAL NEUROLOGO

Luigi Ferini Strambi

Universitagrave Vita-Salute San Raffaele Milano

PARAMETRI FISIOLOGICI PER LA DEFINIZIONE PARAMETRI FISIOLOGICI PER LA DEFINIZIONE DEL SONNODEL SONNO

CM S D

R

IPNOGRAMMAIPNOGRAMMA

Pre - sleep - WPre - sleep - W SWSSWS REM - sleepREM - sleep

Post - sleep - WPost - sleep - W

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

BRAUN et al Brain (1997)

Dijk and Edgar 1999 Lung Biology in Health and Disease vol133

Arousal

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

PARAMETRI FISIOLOGICI PER LA DEFINIZIONE PARAMETRI FISIOLOGICI PER LA DEFINIZIONE DEL SONNODEL SONNO

CM S D

R

IPNOGRAMMAIPNOGRAMMA

Pre - sleep - WPre - sleep - W SWSSWS REM - sleepREM - sleep

Post - sleep - WPost - sleep - W

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

BRAUN et al Brain (1997)

Dijk and Edgar 1999 Lung Biology in Health and Disease vol133

Arousal

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

IPNOGRAMMAIPNOGRAMMA

Pre - sleep - WPre - sleep - W SWSSWS REM - sleepREM - sleep

Post - sleep - WPost - sleep - W

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

BRAUN et al Brain (1997)

Dijk and Edgar 1999 Lung Biology in Health and Disease vol133

Arousal

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Pre - sleep - WPre - sleep - W SWSSWS REM - sleepREM - sleep

Post - sleep - WPost - sleep - W

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

ACTIVATION

High DEACTIVATION

Low DEACTIVATION

BRAUN et al Brain (1997)

Dijk and Edgar 1999 Lung Biology in Health and Disease vol133

Arousal

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Dijk and Edgar 1999 Lung Biology in Health and Disease vol133

Arousal

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Arousal

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

SleepSleep No sleepNo sleep

acuteacutesleepsleep

deprivationdeprivation

Cortisol Cortisol (microgdl)(microgdl)

Thyrotropin Thyrotropin (microUml)(microUml)

ProlactinProlactin(ngml)(ngml)

Growth Growth HormoneHormone

(microgL)(microgL)

Clock TimeClock Time

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

10 14 18 22 02 06 10 10 14 18 22 02 06 10

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

0

5

10

15

20

25

0

5

10

15

20

0

5

10

15

20

01

02

03

04

05

10 14 18 22 02 06 10 10 14 18 22 02 06 10

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Cortisol rhythm

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Lange et al (2003) Psychosomatic Medicine 65 831-835

Sleep loss impairs the human antibody response to hepatisis A vaccination

total loss of sleep in the night following vaccination impairs immune response 28 days later

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Response to influenza vaccination is impaired in individuals with chronic partial sleep restriction

Spiegel et al (2002) JAMA 288 1471-1472

Sleep restriction to 4 hoursnight for 4 days before and 2 days after vaccination impairs immune response to vaccination

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Structural MRI of the brains of humans with extensive navigation experience licenced London taxi drivers were analysed and compared to those of control subjects who did not drive taxiThe posterior hippocampi of taxi drivers were significantly larger relative to those of controlsA more anterior hippocampal region was larger in controls than in taxi drivershellip

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Mechanism of brain damage

Neurogenic or vasogenic

Potential contributors of cognitive impairment

Hypoxemia or sleep fragmentation

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Sleep-Disordered Breathing Hypoxia and Risk of Mild Cognitive Impairment and Dementia in Older Women Yaffe K et al JAMA 306 613-19 2011

Compared with the 193 women without sleep-disordered breathing the 105 women (352) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (adjusted odds ratioAOR = 185) Elevated oxygen desaturation index (ge15 eventshour) and high percentage of sleep time (gt7) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR= 171 and 204 respectively) Measures of sleep fragmentation (arousal index and wake after sleep onset) were not associated with risk of cognitive impairment

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

The hippocampus is one of the main and most consistently reported brain regions among the neural correlates of mild cognitive impairmenthelliphelliphelliphellip

No medications are known to prevent the progression of mild cognitive impairment to Alzheimerrsquos disease so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Neurocognitive Function

bull Odds of optimal users exhibiting normalization of memory function were 79 times (p 001) the odds of poor users

bull Normalization of memory abilities in

21 of poor users

44 of moderate users

68 of optimal users

Zimmerman et al CHEST 2006

58 memory impaired OSA

patients

Neuropsychological Testing

Neuropsychological Testing + Compliance

3 months CPAP

Poor Userslt2 hnight

Moderate Users2-6 hnight

Optimal Usersgt6 hnight

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

International Classification of Sleep Disorders 2005

bull INSOMNIAbull SLEEP-RELATED BREATHING DISORDERSbull HYPERSOMNIA OF CENTRAL ORIGINbull CIRCADIAN RHYTHM SLEEP DISORDERSbull PARASOMNIASbull SLEEP RELATED MOVEMENT DISORDERS

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Luyster F et al

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Chen R et al

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

PERIODIC LEGS MOVEMENTS (PLMs)

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Restless Legs Syndrome

Essential criteria

1) An urge to move the legs2) that is present at rest

3) relieved by movement and4) demonstrates a circadian

pattern (peak symptomsoccurring at night or in the

evening)

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Diagnostic criteria for RLS- Non essential but common features

bull Family history

bull Response to dopaminergic therapy

bull Experience of PLM during sleep or during wakefulness

bull Sleep disturbance

bull An increase in severity with advancing age

Allen et al Sleep Med 2003

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

PD patient 69 y male

AHI= 21 PLMI= 28

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Eur Res J in press

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

In RLS PLMs induce a repetitive rise in blood pressure and heart rate

RLS and periodic limb movementsRLS and periodic limb movements

Pennestri MH et al Neurology 2007681213ndash1218Siddiqui F et al Clin Neurophysiol 20071181923ndash1930

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

RLS patients show significant sleep microstructure abnormalities (increased cortical arousals)

Acute pramipexole administration seems to exert no action on these abnormalities and the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of pre-sleep RLS symptoms and PLMS

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

PLMS

CORTICAL AROUSALS

AUTONOMIC AROUSAL

INSOMNIA CV RISK

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Narcolepsy Repeated refreshing naps of short duration (lt1hr)

Recurrent hypersomnia Recurrent episodes of 18-20 hrs lasting 3-20 days 1-3 years

Idiopatic hypersomnia Prolonged (1-2 hrs) sleep episodes of NREM sleep and major sleep episode gt8 hrs

Post-traumatic hypersomnia

As above However the sleepiness is most evident in the immediate post-traumatic period and resolves over weeks to months

OSA Sleepiness in a relaxing situation unrefreshing naps (variable duration)

Insufficient sleep syndrome Sleepiness is not present during weekends or vacation time

SLEEPINESS CHARACTERISTICSSLEEPINESS CHARACTERISTICS

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

NarcolepsyNarcolepsy

A disease characterized by loss of clear A disease characterized by loss of clear boundaries between sleep amp wakeboundaries between sleep amp wake

Narcolepsy is characterized by severe Narcolepsy is characterized by severe sleepiness frequent unwanted transitions sleepiness frequent unwanted transitions into sleep during wakefulness as well as into sleep during wakefulness as well as frequent periods of awakenings during frequent periods of awakenings during sleepsleep

Patients with narcolepsy can quickly enter Patients with narcolepsy can quickly enter REM sleep at anytime of the dayREM sleep at anytime of the day

Patients also experience REM sleep-like Patients also experience REM sleep-like episodes intruding into wakefulness such episodes intruding into wakefulness such as loss of muscle tone while awake a as loss of muscle tone while awake a condition known as cataplexycondition known as cataplexy

Dauvilliers et al Neurology 2001572029-2033 Okun et al Sleep 20022527-35

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

NarcolepsyCataplexy PrevalenceNarcolepsyCataplexy Prevalence Estimates Differ Between Ethnic GroupsEstimates Differ Between Ethnic Groups

0

010

020

030

040

050

060

Hublin et al Ann Neurol 199435709 Silber et al Sleep 200225197 Honda Sleep Res 19798191 Tashiro et al J Sleep Res 19921228 Wilner et al Hum Immunol 19882115 Ohayon et al Neurology 2002 581926 Zeman et al BMJ 2004 329724

Western EuropeNorth America

Japan Israel

o

f p

op

ula

tio

n

0026

016

00020035

059Low estimate

High estimate

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

NarcolepsyNarcolepsy Constellation of SymptomsConstellation of Symptoms

Excessive daytime sleepinessExcessive daytime sleepiness

Cataplexy and other REM phenomena Cataplexy and other REM phenomena

Hypnagogichypnopompic hallucinationsHypnagogichypnopompic hallucinations

Sleep paralysisSleep paralysis

Fragmented sleepFragmented sleep

Automatic behaviors Automatic behaviors

Guilleminault Narcolepsy syndrome In Principles and Practice of Sleep Medicine 1994

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Hypocretin Deficiency Hypocretin Deficiency in Human Narcolepsyin Human Narcolepsy

0

100

200

300

400

500

600

700

Control(n=47)

Narcolepsywith

cataplexy(n=101)

Narcolepsywithout

cataplexy(n=20)

CS

F h

yp

ocr

etin

(p

gm

L)

Mignot et al Arch Neurol 2002591553

47 10

3

88

18

0

3

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

Pre-motor features of Parkinsons disease the Honolulu-Asia Aging Study experience

Ross GW et al Mov Disord 2012

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men born 1900-1919 Beginning in 1965 environmental life-style and physical characteristics including many features associated with pre-motor Parkinsons disease (PD) were ascertained at examinations over 40 years

Impaired olfaction constipation slow reaction time excessive daytime sleepiness and impaired executive function were all associated with future development of PD andor with increased likelihood of either incidental Lewy bodies

Compared with persons without any those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD

CPAP improves sleep and daytime sleepiness in patients with PD and sleep

apnea

- Randomized placebo-controlled cross over study

-38 PD patients treated for 6 weeks

- CPAP treated patients showed significantly decrease in AHI and Arousal index and increase in N3 stage

- CPAP also reduced daytime sleepiness measured by MSLT

Neikrug AB et al Sleep 37 177-85 2014

CLASSIFICAZIONE INTERNAZIONALE PARASONNIE

DISTURBI DELLrsquoAROUSAL

bull SONNAMBULISMO

bull PAVOR NOCTURNUS (INCUBI)

DISTURBI DEL PASSAGGIO SONNO-VEGLIA

bull MOVIMENTI RITMICI DEL SONNO (STEREOTYPED PARASOMNIAS)

bull MIOCLONIE IPNICHE

bull SONNILOQUIO

PARASONNIE ASSOCIATE AL SONNO REM

bull SOGNI TERRIFICI

bull REM SLEEP BEHAVIOR DISORDER

ALTRE PARASONNIE

bull BRUXISMO

bull ENURESI NOTTURNA

bull DISFAGIA NOTTURNA SALIVARE

bull DISTONIA PAROSSISTICA NOTTURNA

bull MORTE IMPROVVISA IN SONNO (DA CAUSA SCONOSCIUTA)

bullSINDROME DELLA MORTE IMPROVVISA DEL LATTANTE

bull SINDROME DA IPOVENTILAZIONE CENTRALE CONGENITA

bull MIOCLONO BENIGNO NEONATALE IN SONNO

Sleep TerrorsSleep TerrorsDifferential diagnosis

SLEEPTERRORS

NIGHTMARES

Part of the night First third Last thirdMajor motoractivity

++ +-

Anxiety +++ ++Vocalization ++ +Autonomicdischarge

+++ +

Intellectual function -(Confusion) +(Good)

Rem Sleep Behavior Disorder (RBD)

bull 1986 ndash 5 patients ndash Mahowald et al

bull RBD is characterized by the intermittent loss of Rem sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation

REM SLEEP BEHAVIOR DISORDERREM SLEEP BEHAVIOR DISORDER

Some clinical aspects of RBDSome clinical aspects of RBD

Estimated prevalence 004-05

Male prevalence (MF 91)

Age of onset 526 16 yrs

Altered dream content or enacting behaviors 92

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
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• Slide 40
• Slide 41
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• Slide 44
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• Slide 47
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• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

CLASSIFICAZIONE INTERNAZIONALE PARASONNIE

DISTURBI DELLrsquoAROUSAL

bull SONNAMBULISMO

bull PAVOR NOCTURNUS (INCUBI)

DISTURBI DEL PASSAGGIO SONNO-VEGLIA

bull MOVIMENTI RITMICI DEL SONNO (STEREOTYPED PARASOMNIAS)

bull MIOCLONIE IPNICHE

bull SONNILOQUIO

PARASONNIE ASSOCIATE AL SONNO REM

bull SOGNI TERRIFICI

bull REM SLEEP BEHAVIOR DISORDER

ALTRE PARASONNIE

bull BRUXISMO

bull ENURESI NOTTURNA

bull DISFAGIA NOTTURNA SALIVARE

bull DISTONIA PAROSSISTICA NOTTURNA

bull MORTE IMPROVVISA IN SONNO (DA CAUSA SCONOSCIUTA)

bullSINDROME DELLA MORTE IMPROVVISA DEL LATTANTE

bull SINDROME DA IPOVENTILAZIONE CENTRALE CONGENITA

bull MIOCLONO BENIGNO NEONATALE IN SONNO

Sleep TerrorsSleep TerrorsDifferential diagnosis

SLEEPTERRORS

NIGHTMARES

Part of the night First third Last thirdMajor motoractivity

++ +-

Anxiety +++ ++Vocalization ++ +Autonomicdischarge

+++ +

Intellectual function -(Confusion) +(Good)

Rem Sleep Behavior Disorder (RBD)

bull 1986 ndash 5 patients ndash Mahowald et al

bull RBD is characterized by the intermittent loss of Rem sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation

REM SLEEP BEHAVIOR DISORDERREM SLEEP BEHAVIOR DISORDER

Some clinical aspects of RBDSome clinical aspects of RBD

Estimated prevalence 004-05

Male prevalence (MF 91)

Age of onset 526 16 yrs

Altered dream content or enacting behaviors 92

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
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• Slide 17
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• Slide 23
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• Slide 27
• Slide 28
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• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

Sleep TerrorsSleep TerrorsDifferential diagnosis

SLEEPTERRORS

NIGHTMARES

Part of the night First third Last thirdMajor motoractivity

++ +-

Anxiety +++ ++Vocalization ++ +Autonomicdischarge

+++ +

Intellectual function -(Confusion) +(Good)

Rem Sleep Behavior Disorder (RBD)

bull 1986 ndash 5 patients ndash Mahowald et al

bull RBD is characterized by the intermittent loss of Rem sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation

REM SLEEP BEHAVIOR DISORDERREM SLEEP BEHAVIOR DISORDER

Some clinical aspects of RBDSome clinical aspects of RBD

Estimated prevalence 004-05

Male prevalence (MF 91)

Age of onset 526 16 yrs

Altered dream content or enacting behaviors 92

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

Rem Sleep Behavior Disorder (RBD)

bull 1986 ndash 5 patients ndash Mahowald et al

bull RBD is characterized by the intermittent loss of Rem sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation

REM SLEEP BEHAVIOR DISORDERREM SLEEP BEHAVIOR DISORDER

Some clinical aspects of RBDSome clinical aspects of RBD

Estimated prevalence 004-05

Male prevalence (MF 91)

Age of onset 526 16 yrs

Altered dream content or enacting behaviors 92

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

REM SLEEP BEHAVIOR DISORDERREM SLEEP BEHAVIOR DISORDER

Some clinical aspects of RBDSome clinical aspects of RBD

Estimated prevalence 004-05

Male prevalence (MF 91)

Age of onset 526 16 yrs

Altered dream content or enacting behaviors 92

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

Some clinical aspects of RBDSome clinical aspects of RBD

Estimated prevalence 004-05

Male prevalence (MF 91)

Age of onset 526 16 yrs

Altered dream content or enacting behaviors 92

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

Clinical RBD course

RBD

acute

chronic

alcohol (withdrawal)

tryciclic antidepressants (intoxication or

withdrawal)

anti-MAO caffeine (intoxication)

25 Idiopathic form

75 symptomatic form(neurological diseases)

Initial manifestation

Consequent symptom

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

bull Impairment of cortical activitybull Neuropsychological deficitsbull Autonomic dysfunctionsbull Olfactory deficits

Does the idiopathic form of RBD really exist

NEUROLOGY 2005 64780-786

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

INCREASED AGGRESSIVE DREAM CONTENT WITHOUT INCREASED DAYTIME AGGRESSIVENESS

IN REM SLEEP BEHAVIOR DISORDER

ML Fantini A Corona S Clerici and L Ferini-Strambi

Neurology 2005

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 11
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59

RESULTS ndash RESULTS ndash Daytime aggressivenessDaytime aggressiveness

bull Two patients with RBD and 4 controls had an AQ score gt96 which is considered suggestive of daytime aggressiveness

RBD

patients Controls p

AQ total score 699 plusmn 161 738 plusmn 203 037

Physical Aggression 165 plusmn 64 204 plusmn 83 0034

Verbal Aggression 150 plusmn 42 144 plusmn 40 059

Anger 179 plusmn 65 173 plusmn 60 067

Hostility 204 plusmn 54 216 plusmn 62 038

bull No between-group difference in overall daytime aggressiveness

bull Patients with RBD showed lower score on ldquoPhysical Aggressionrdquo than controls

RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

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RESULTS ndash RESULTS ndash Dream contentDream content

bull Compared to control subjects RBD showed

Dreams with at least one aggression (66 vs 15 plt000001)

ratio AggressionFriendliness interactions (89 vs 44 plt00001)

frequency of Animal characters (19 vs 4 p=00001)

No Dreams with at least one element of sexuality (0 vs 9 plt00001)

RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

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RBD DIFFERENTIAL DIAGNOSES

Sleepwalking and sleep terrors (possibility of overlap)

Nocturnal seizures Obstructive sleep apnea (OSA) with

agitated REM-related arousals Psychogenic dissociative disorders

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