1. 2 objectives 1.recognize the clinical presentation of narcolepsy 2.understand the consequences of...
TRANSCRIPT
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Objectives
1. Recognize the clinical presentation of narcolepsy2. Understand the consequences of narcolepsy3. Learn about our evolving understanding of
narcolepsy4. Explore the pathophysiology of narcolepsy5. Review standard diagnostic criteria for narcolepsy6. Compare current treatments for narcolepsy and
discuss possible future treatments
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Clinical Presentation of Narcolepsy
• Prevalence
• Level of Disability
• Symptoms
• Consequences
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ICSD-2 Criteria for Narcolepsy
• Characterized by excessive sleepiness• Two variants are described:
– Narcolepsy With Cataplexy– Narcolepsy Without Cataplexy
• A third diagnosis, Narcolepsy Due to Medical Condition, is used when the criteria for narcolepsy are met and the onset of the disorder appears to be the consequence of a medical condition
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0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.2
Israel Finland NorthernCalifornia
SouthernCalifornia
Japan MultipleSclerosis
(US)
Pe
rce
nta
ge
of
Po
pu
lati
on
Narcolepsy With Cataplexy: Prevalence
Data from Mignot, 1998
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Quality of Life in Narcolepsy
0
10
20
30
40
50
60
70
80
90
100
PhysicalFunctioning
RoleLimitations
Due toPhysicalProblems
Bodily Pain GeneralHealth
Vitality SocialFunctioning
RoleLimitations
Due toEmotionalProblems
MentalHealth
SF-
36 S
core
s Narcoleptics
MultipleSclerosis
Parkinson'sDisease
Post PartumDepression
Controls
Data From Da Costa et al 2005, Riazi et al 2003 and Beusterien et al 1999
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TetradPentad
Clinical Presentation: Symptoms
• Excessive daytime sleepiness (EDS)
• Cataplexy• Hypnagogic hallucinations• Sleep paralysis
• Fragmented nocturnal sleep
• Other associated features
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Symptom Prevalence
0
10
20
30
40
50
60
70
80
90
100
Sleepiness HypnagogicHallucinations
Sleep Paralysis DisruptedSleep
Cataplexy
Per
cent
age
of P
atie
nts
From ICSD-2 except
cataplexy estimate
from Anic-
Labat et al 1999
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Faces of Sleepiness
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Clinical Sleepiness
“I’ve fallen asleep pretty much everywhere. I fall asleep at work, at the movies, in the car and at home. My most impressive story is that I fell asleep at the basketball arena during a playoff game. It was a close game and very exciting, but I was unable to keep my eyes open.”
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Excessive Daytime Sleepiness (EDS)
• Sleep attacks on a background of chronic sleepiness or fatigue
• Frequent napping, usually refreshing• Memory lapses and automatic behaviors• Impaired attention / concentration
– Decreased work performance
– Increased drowsy driving crashes
• Visual disturbances
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Quantification of Sleepiness
0
5
10
15
20
25
MSLT MWT Epworth
Sc
ore Normal
Narcoleptic
From Johns 2000
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Narcolepsy Controls
Do you drive? 48% 63%
Fall asleep driving 66 6
Cataplexy driving 29 0
Sleep paralysis driving 12 0
Frequent near accidents 67 0
Led to accidents 37 5
Higher insurance 16 1
Suspended license 7 4
Sleepiness While Driving
From Broughton et al 1981
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0123456789
10
Controls EDS, No Narcolepsy Narcolepsy
Per
cent
age
of O
bsta
cles
Hit
in
Dri
ving
Sim
ulat
or
Adapted from Findley, 1995
Driving Simulator Errors
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Percentage of Patients with Sleep Related Motor Vehicle Accidents
0
10
20
30
40
50
60
ObstructiveSleep Apnea
Narcolepsy OtherSleepiness
ControlPerc
enta
ge o
f Pat
ient
s
Men
Women*
*Significantly different from Controls
* *
Data from Aldrich, 1989
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Neurocognitive Effects
• Normal short- and long-term memory when controlled for alertness– Auditory Verbal Learning Test – Knox Cube– Rey Complex Figure Test – Symbol Digits Modality Test – Wechsler Memory Scale
• Variable attention and concentration– Strub and Black’s List of Letters
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50
60
70
80
90
100
10:00 AM 12 noon 2:00 PM 4:00 PM 6:00 PM
300
400
500
600
700
800
10:00 AM 12 noon 2:00 PM 4:00 PM 6:00 PM
Wilkinson Addition Test
Digit Symbol Substitution Test
Adapted from Mitler et al 1982
Performance Deficits
Control
Narcoleptic
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Cataplexy
• Muscle weakness triggered by emotions– Joking, laughter, excitement, anger– Brief duration, mostly bilateral
• May affect any voluntary muscle– Knee / leg buckling, jaw sagging, head
drooping, postural collapse
• Consciousness maintained at the start
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0
10
20
30
40
50
60
70
80
90
100
Laughing Joking Anger Stress Sex
Per
cent
age
of P
atie
nts
Adapted from Anic-Labat 1999
Triggers for Cataplexy
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0
20
40
60
80
100
120
Legs / knees Jaw Slurred speech Generalized(falling toground)
Pe
rce
nta
ge
of
Pa
tie
nts
Muscles Affected by Cataplexy
Adapted from Anic-Labat 1999
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Clinical Report of Cataplexy
“At some point my friends discovered that I would collapse when I laughed. They invented a game called “flooring Ron” in which they took turns telling jokes. The jokes that made me fall to the ground won the game.”
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• Sleep paralysis– Sudden inability to move on falling
asleep or on awakening– Episodes are generally brief and benign,
end spontaneously – Can cause significant anxiety
Associated Features
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• Hallucinations– Vivid hallucinations at sleep onset
(hypnagogic) or awakening (hypnopompic)– Auditory: sounds, music, someone talking
to them– Visual: colored circles, parts of objects– Can be vividly realistic and anxiety
provoking
Associated Features (cont.)
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• Psychosocial problems
• Depression
• Headaches
• Frequent Misdiagnoses – Major depression
– Thyroid disorder
– Chronic fatigue syndrome
– Schizophrenia
Associated Features (cont.)
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• Dahmen et al 1999 studied 68 narcoleptics– Idiopathic headache syndrome: 81%– Migraine: 54% (64% females, 35% males)
• DMKG Study Group 2003 studied 96 narcoleptics and age-matched controls– Increased frequency of tension-type headache
(60.3% in narcoleptics, 40.7% in controls)– No difference in frequency of migraine (21.9% in
narcoleptics, 19.8% in controls)
Headaches May Be Common In Narcolepsy
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Age of Onset of Symptoms
0
5
10
15
20
25
5 10 15 20 25 30 35 40 45 50 55 60 65 70
Age
Per
cen
tag
e o
f P
atie
nts
Data from Parkes 1985
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• Under-recognized / misdiagnosed– Sleepiness may present as:
• Learning disability• Attention deficit hyperactivity disorder
– Cataplexy may be mislabeled as psychogenic behavior
• May be secondary to other disorders
Prepubertal Narcolepsy
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1880 1900 1920 1940 1960 1980 2000
Syndrome first described, 1877
Amphetamines used for
treatment, 1935
Sleep Onset REM Period, 1960
Canine narcolepsy, 1973
HLA association, 1981
Hypocretin in animals, 1998
Hypocretin in humans, 2000
Narcolepsy Time Line
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The Birth of a Syndrome
• 1880 Gélineau uses term “Narcolepsy”• Case description: 38 year old wine
cask maker• Symptoms include severe sleepiness
and episodes of muscle weakness with laughter
• Described syndrome as a form of neurosis, placing it firmly in the realm of psychiatry for the next 80 years
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Association with REM Sleep
• 1960 Vogel reports that narcoleptic patients transition from waking directly to REM sleep (Sleep Onset REM Periods)
• 1969 Rechtschaffen and Dement write several articles linking symptoms of narcolepsy to REM sleep phenomena
• This linkage stimulates development of the Multiple Sleep Latency Test
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Central EEG
LOC
Occipital EEG
ROC
Chin EMG
R. + L. AT EMG
HR
ECG
VtRIP
Narcolepsy Is Characterized By Sudden Transitions From Wakefulness To REM Sleep
Decreased chin muscle toneRapid Eye Movements
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32Courtesy of GJ Lammers
motoneuron
Descending
Inhibiting
Influences
Ia afferent
5 mV 5 ms 5 mV 5 ms
Awake REM
Motoneuron Inhibition
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Normal and narcoleptic 24-hour PSG recordings
Co
ntr
ol
Un
trea
ted
P
atie
nt
Adapted from Rogers 1994
Sleep / Wake Fragmentation
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Circadian Rhythm Abnormalities
• Compared to controls, narcoleptics have:– Dampened temperature rhythms– A shift to an earlier temperature low point– A reduced sleep latency after temperature
starts to drop
From Mayer et al 1997
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• HLA-DR2 and DQB1*0602 are tightly associated with narcolepsy with cataplexy, as is multiple sclerosis
• Demonstrates a common genetic origin of susceptibility for narcolepsy with cataplexy
• Implicates the immune system in the pathophysiology of narcolepsy, BUT– Narcolepsy is not associated with other autoimmune diseases– IgG oligoclonal bands are not present in narcolepsy– There is no evidence of cellular autoimmunity in narcolepsy
HLA-Narcolepsy Association
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36Peter Hjelmström © 1996
A 3-dimensional model of an HLAmolecule with a bound peptide
HLA-DR andHLA-DQ areassociatedwith narcolepsy
HLA and Narcolepsy
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37Peter Hjelmström © 1996
A 3-dimensional model of an HLA molecule with a bound peptide
• HLA-DR2 or DQB1*0602 is not sufficient to cause narcolepsy
• Additional gene(s) may be required
• Environmental factors play a role
• In some families, a non-HLA gene may confer narcoleptic susceptibility
Genetic Factors in Narcolepsy
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38Data from Mignot et al 2002
HLA DQB1*0602 Association
0
10
20
30
40
50
60
70
80
90
100
Narcolepsy WithCataplexy
NarcolepsyWithout Cataplexy
IdiopathicHypersomnia
Control
Per
cent
age
of p
atie
nts
with
DQ
B1*
0602
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• HLA-DQ is a genuine narcolepsy susceptibility gene– No other gene found in critical 6p21
chromosomal segment– Complex HLA-DQ allelic interactions and
DQB1*0602 dosage effects
• Autoimmune lesion / molecular mimicry• HLA-neurotransmitter systems interaction
Potential Roles of HLA
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• Affects 0.03% to 0.1% of the general population• Most cases of narcolepsy are sporadic
• 1% to 2% of first degree relatives have narcolepsy-cataplexy (relative risk = 20 to 40 times greater than general population)
• Familial clustering occurs in about 10% of cases• Most monozygotic twins are discordant for narcolepsy• Environmental factors are implicated
– Unknown antigen binding with HLA DQB1*0602– Head trauma, virus, toxins– Sleep deprivation, change in sleep / wake cycle
• Developmental factors (puberty, aging)
Environmental and Developmental Factors
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41Reprinted from Cell, Vol. 98(3) Copyright © 1999, with permission from Elsevier Science.
Pathophysiology
• Canine Narcolepsy– Cataplexy
– REM onset
– Sleepiness
– Drug response
• Murine Narcolepsy– Cataplexy
– REM sleep onset
Animal Models
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Hcrtr2Hcrtr2
12q13-2112q13-21
• Defects in the hypocretin / orexin system are responsible for narcolepsy in animal models
• Canine narcolepsy gene– Hypocretin receptor 2
(Hcrtr2)
• Mouse narcolepsy– Deletion of hypocretin
peptide genes
Animal Models
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Hypocretin System
HypocretinContainingCells of the
LateralHypothalamus
LocusCoeruleus
LocusCoeruleus
CortexLayerVIb
CortexLayerVIb
LaterodorsalTegmentalNucleus
LaterodorsalTegmentalNucleus
ArcuateNPY
Inputs
ArcuateNPY
Inputs
Other Peptides:CRF, CCK, MCH, etc
Other Peptides:CRF, CCK, MCH, etc
From de Lecea and Sutcliffe, 2005
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Normal
Hypocretin Cell Loss in Human Narcolepsy
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
Nu
mb
er
of
Ne
uro
ns
NormalNarcolepsy
Narcolepsy
Photomicrographs courtesy J Siegel, UCLA, 2000Data from Thannickal et al 2000
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Thalamocortical Loops:EEG synchronization
Amygdala & Limbic System:Emotional triggering of cataplexy
Spinal Cord Motoneurons:REM sleep atonia, cataplexy
Pons:REM sleep generator
Hypothalamus:Integration ofsleep andcircadianinfluences
Neuroanatomy
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Basal Forebrain:Ach, Adenosine
Amygdala & Limbic System:Ach, Dopamine
Spinal Cord:Glycine
Posterior Hypothalamus:Hypocretin
Cortex:Ach, Dopamine
Brainstem:Ach cell groupMonoamine cell groups
Neurotransmitters
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LATERALHYPOTHALAMU
S
LATERALHYPOTHALAMU
S
SUBPARAVENTRICULAR
ZONE
Hypothalamic Regulation of Sleep
SUPRACHIASMATIC
NUCLEUS
SUPRACHIASMATIC
NUCLEUS
DORSOMEDIALNUCLEUS OF THEHYPOTHALAMUS
DORSOMEDIALNUCLEUS OF THEHYPOTHALAMUS
VENTROLATERAL PREOPTIC NUCLEUS
CLOCK INFORMATION
After Saper et al 2005
SLEEP WAKE
HYPOCRETIN
CONTAINING
NEURONS
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Summary of Pathophysiology
• Sleep physiology -- clinical signs– Disassociated REM sleep features (paralysis, hallucinations)
– Inability to maintain wakefulness or any sleep stage
– No intrinsic circadian abnormality
• Neuroanatomy / Neurochemistry -- diagnostic value– Loss of hypocretin containing cells in the
perifornical area
– Pontine, hypothalamic and limbic abnormalities
– Secondary cholinergic and aminergic dysfunctions
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Pathophysiology (cont.)
• Genetic– Familial aspects of human narcolepsy– HLA DR and DQ association in humans– Hypocretin gene mutations in animal models
and in very rare human cases
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Approach to the Patient With Narcolepsy
• Know the criteria for diagnosis
• Clinical assessment of sleepiness and cataplexy
• Polysomnographic and MSLT criteria for diagnosis
• Treatment options
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ICSD-2 Criteria for Narcolepsy
• Characterized by excessive sleepiness• Should, whenever possible, be confirmed by a
polysomnogram and Multiple Sleep Latency Test • Alternatively, low or absent hypocretin-1 levels in
the cerebrospinal fluid may be used to confirm the diagnosis
• Two variants are described: – Narcolepsy With Cataplexy– Narcolepsy Without Cataplexy
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Evaluation• History
– Sleepiness, cataplexy, other disassociated REM sleep features
• Polysomnography (PSG)– Exclude other causes for EDS (insufficient sleep,
apnea)– Identify and treat associated conditions
• Multiple Sleep Latency Test (MSLT)– Objective sleepiness– Sleep onset REM periods (SOREMPs)
• CSF Hypocretin levels
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• Does the patient look sleepy?
• Description of EDS– Frequency, age of onset,
circumstances
– Fatigue versus sleepiness
• Specific examples– Work, social, situations, driving
– Corroboration
• Subjective sleepiness scales– Epworth Sleepiness Scale
Clinician’s Assessment of EDS
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• Appropriate triggering events• Characteristic sites of muscle weakness• Consciousness is maintained initially• Usual duration is less than 2 minutes• In very rare cases, strong emotion or
withdrawal from adrenergic or serotoninergic medications may provoke episodes of cataplexy in succession termed status cataplecticus lasting for many minutes up to an hour
Criteria for Cataplexy
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• Short sleep latency• Sleep onset REM period in 50% of
narcoleptics• Sleep fragmentation (REM and NREM)
– Increased number of arousals– Increased stage 1 sleep– Low sleep efficiency
• Frequently associated with periodic limb movements
Polysomnographic Findings
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Polysomnographic Findings
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Frequency of Periodic Limb Movements in Sleep Disorders
0
5
10
15
20
25
Narcolepsy Sleep Apnea Insomnia
Lim
b M
ovem
ent I
ndex
(2
nd N
ight
)
Data from Hornyak et al 2005
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R. + L. AT EMG
Central EEG
LOC
ROC
Chin EMG
ECG
HR
VtRIP
Time in seconds
Periodic Limb Movements of Sleep
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59
AASM Guidelines for the Multiple Sleep Latency Test (MSLT)
• Standardized protocol– Five naps at 2 hour intervals; 4 nap test only if 2 SOREMPs are
recorded– Always performed after a nocturnal polysomnogram ideally with
a minimum of 6 hours of sleep– Rooms should be dark, quiet and at a comfortable temperature– After appropriate withdrawal of any psychotropic drugs
• Stimulants withdrawn 2 weeks prior to test
– No smoking 30 minutes prior to each nap– No vigorous physical activity on the day of the test– No caffeine or exposure to bright sunlight
From Littner et al 2005
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MSLT Practice ParametersThe MSLT is: • A validated objective measure of the tendency to
fall asleep• Indicated as part of the evaluation of patients
with suspected narcolepsy to confirm the diagnosis
• May be indicated in idiopathic hypersomnia• Not routinely indicated for sleep apnea, insomnia
or circadian rhythm disorders
From Littner et al 2005
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Mean Sleep Latency on MSLT
From Arand et al 2005
0
2
4
6
8
10
12
14
16
18
Narcolepsy IdiopathicHypersomnia
ObstructiveSleep Apnea
Normals FourNaps
Normals FiveNaps
Sle
ep
La
ten
cy (
Min
ute
s)
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Central EEG
LOC
Occipital EEG
ROC
Chin EMG
R. + L. AT EMG
HR
ECG
VtRIP
Sleep Onset REM Period
10 seconds
REM
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SOREMPs in Narcolepsy
• For 2 or more SOREMPs during MSLT:– Sensitivity was 0.79– Specificity was 0.98
From Arand et al 2005
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• Sleep disruption and other sleep disorders
• Sleep deprivation / extension
• Circadian factors / shift work
• Age-related effects
• Hypnotic agents / alcohol
• Stimulants / caffeinated substances
• Psychological stimulation
Factors Affecting MSLT
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Effect of Age on MSLT Latency in Normal Subjects
8
9
10
11
12
13
14
15
16
17
10 20 30 40 50 60 70 80
Age
Me
an
La
ten
cy
(M
inu
tes
)
From Arand et al 2005
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Other Tests• Not diagnostic
– Single daytime nap test or clinical EEG
– HLA typing– Response to stimulants – Pupillometry – Maintenance of
wakefulness test (MWT)– Subjective sleepiness
scales
• Possibly diagnostic– 24-hour continuous
recording
• Diagnostic– Measurement of CSF
hypocretin levels
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Effects of Age on MWT in Normals
10
15
20
25
30
35
40
30-39 40-49 50-59 60-69
Age
Me
an
La
ten
cy
(M
inu
tes
)
40 Minute Protocol 20 Minute Protocol
From Arand et al 2005
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Cerebrospinal Fluid Hypocretin-1 Levels
0
50
100
150
200
250
300
350
400
NarcolepsyWith
Cataplexy
NarcolepsyWithout
Cataplexy
IdiopathicHypersomnia
ObstructiveSleep Apnea
Controls
CS
F H
yp
oc
reti
n (
pg
/mL
)
From Mignot et al 2002
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• Narcolepsy with cataplexy– Excessive daytime sleepiness with definitive cataplexy,
confirmed by polysomnogram followed by MSLT or CSF hypocretin-1 levels below 110 pg/mL
• Narcolepsy without cataplexy– Excessive daytime sleepiness, no clear cataplexy with positive
polysomnogram and MSLT (sleep latency less than 8 min; 2 or more SOREMPs)
• Narcolepsy due to medical condition– Excessive daytime sleepiness, with or without cataplexy, positive
MSLT, and medical or neurologic condition associated with narcolepsy
ICSD-2 Diagnostic Criteria
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Differential Diagnosis for Narcolepsy
• Sleep related breathing disorders
• Behaviorally induced insufficient sleep syndrome
• Idiopathic hypersomnia
• Depression, fatigue, malingering
• Drug use or drug withdrawal
• Delayed sleep phase syndrome
• Malingering and secondary gain
• Periodic limb movement disorder
• Kleine-Levin syndrome
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Therapeutic Approaches
• Pharmacotherapy– Sleepiness
– Cataplexy
– Fragmented nocturnal sleep
– Compliance issues
• Behavioral interventions
• Psychosocial and educational interventions
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Sleepiness• Stimulants
– Only effective treatment for EDS
– Establish accurate diagnosis prior to treatment
• Treatment objectives– Alleviate daytime sleepiness
– Not to enhance performance on attention tasks
• Effective medications:– Modafinil, methylphenidate,
methamphetamine, dextroamphetamine
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Presynaptic Postsynaptic
tyramine dopa dopamine
Methylphenidate and possibly modafinilBlock re-uptake
Amphetamine-like stimulants inhibit VMAT, increase
dopamine release
GHB reduces cell firing but does not inhibit dopamine
synthesis
UUUU
UUUU
Action of Stimulants
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Neurotransmitters– Dopamine– Histamine– Hypocretins
Pharmaceutical Agents– Amphetamine-like
compounds– H3 receptor agonists– Hypocretin agonists– Sodium oxybate
Potential Wake-Promoting Systems
See Mignot et al 2002 for review
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Treatment of Sleepiness• Modafinil
– 200 to 800 mg/day– Moderate efficacy, long half life– Best side effect profile– Schedule IV, most expensive
• Methylphenidate– 5 to 100 mg/day– Short half life formulation, variable dosing– Long acting formulation available– Used alone or in combination– Sympathomimetic effects, mood alterations
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Treatment of Sleepiness
• Dextroamphetamine / Methamphetamine– 5 to 100 mg/day
– Short and long half life formulation
– Most efficacious
– Sympathomimetic effects, mood alterations
– Schedule II, most difficult to obtain
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Treatment of SleepinessModafinil
Daily Dose Schedule Cost Efficacy Formulation Side Effects
200-800 IV $$$$ + Long +
Methylphenidate
Daily Dose Schedule Cost Efficacy Formulation Side Effects
10-150 II $$ +++ Short and Long
++
Dextroamphetamine
Daily Dose Schedule Cost Efficacy Formulation Side Effects
5-100 II $$ +++ Short and Long
++
Methamphetamine
Daily Dose Schedule Cost Efficacy Formulation Side Effects
5-100 II $$ +++ Short and Long
++
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• Establish realistic goals on an individual basis• Start with low dose and safest agent• Titration to optimal dose within 10 days• Supplement with short-acting stimulant if
needed• Expect drug and dose response variability• It may be necessary to use high doses and /
or switch to amphetamine-derivatives
Initiating Therapy for Sleepiness
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79Adapted from US Modafinil in Narcolepsy Multicenter Study Group 2000.
Reduction of Sleepiness -- Modafinil
0
2
4
6
8
10
12
14
16
18
MSLT MWT Epworth
Placebo
Modafinil200 mg
Modafinil400 mg
*Significantly different from
placebo (p< 0.05)
*
*
**
*
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Un
trea
ted
Tre
ated
Adapted from Rogers et al 1994
Reduction of Napping
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81Adapted from Mitler et al1991
Pharmacotherapy: Relative Efficacy
0
10
20
30
40
50
60
70
80
90
100
Pe
rce
nt
of
No
rma
l
Baseline Treatment
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-5
0
5
10
15
20
25
Physicalfunctioning
Rolelimitations-
physical
Bodily pain GeneralHealth
Vitality Socialfunction
Rolelimitation-emotional
Mentalhealth
SF
-36
Ch
ang
e in
Sco
re
Placebo (n=163)
Modafinil 200 mg
Modafinil 400mg
*
*
**
**
*p<0.05 between treatment group and placebo
Adapted from Beusterien et al 1999
Quality of Life
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• Treatment failures– Compliance
– Tolerance
– Other medical, psychiatric or sleep disorders
• Pregnancy and nursing
• Anesthesia
• Recreational drugs
Long-term Management
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Compliance With Stimulant Medication
0
20
40
60
80
100
Full Amount Between 80and 99%
Between 50and 80%
Less Than50%
Portion of Prescribed Dose Taken
Per
cent
age
of P
atie
nts
Adapted from Rogers et al 1997
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• Tricyclic antidepressants– Protriptyline (10 to 60 mg/day)
– Clomipramine / Imipramine (25 to 150 mg/day)
– Anti-cholinergic side effects
• Selective serotonin re-uptake inhibitors– Fluoxetine / Paroxetine (20 to
60 mg/day)
– Better tolerated but higher dose often needed
• Sodium oxybate – 3-9 g/night
• Miscellaneous treatments– Venlafaxine (75 to 150 mg/day)
– Reboxetine (not available in US)
Cataplexy and Disassociated REM Sleep Features
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Presynaptic Postsynaptic
norepinephrinenorepinephrine
UUUU
UUUU
serotoninserotonin
dopaminedopamine
Protriptyline, imipramine and desipramine
Block NE re-uptake
Protriptyline, imipramine and desipramine
Block NE re-uptake
Clomipramine, fluoxetine Block serotonin re-uptake
Clomipramine, fluoxetine Block serotonin re-uptake
GHB reduces cell firing but does not inhibit dopamine
synthesis
GHB reduces cell firing but does not inhibit dopamine
synthesis
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0
5
10
15
20
25
Baseline 10 mg 30 mg
Cat
aple
xy S
ever
ity S
cale
Dose
Cataplexy Treatment -- Protriptyline
Adapted from Mitler et al 1990
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Cataplexy Treatment – GHB
Data from Xyrem International Study Group 2005
0
5
10
15
20
25
30
35
Placebo 4.5 g 6g 9 g
Ep
iso
des
of
Cat
aple
xy P
er
Wee
k
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• Not all patients require therapy• Side effects and complications limit use• Select drug and timing of administration to
match its sedating or stimulating effects (e.g. sedating antidepressants at bedtime)
• Pregnancy and nursing
Treatment of Cataplexy
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• Generally untreated• If treated, will not normalize daytime alertness• Hypnotic compounds or sedating
antidepressants can be used• Avoid hypnotics with carryover effects• Gamma hydroxybutyrate is also effective
Fragmented Nocturnal Sleep
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Always ask your patients “Are you having any difficulties taking your medication?”
Compliance
• Barrier– Unacceptable side
effects
– Complex regimen
– Expensive / unavailable medications
– Patient and family prejudice
• Solution– Change medication or
dosing
– Simplify regimen
– Change medications or involve social
services
– Education
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Behavioral Interventions
• Have limited efficacy by themselves (e.g. napping, improving sleep habits)
• Sleepiness / fragmented nocturnal sleep is exacerbated by:– Poor sleep hygiene– Shift work– Alcohol and other recreational drugs
• Avoid driving and dangerous work when sleepy
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93Adapted from Rogers et al 2001
Least sleepy
Very sleepy
Moderately sleepy
-20
-10
0
10
20
30
40
Severity Group
Re
du
cti
on
of
Un
pla
nn
ed
N
ap
s (
min
ute
s/d
ay
)Napping and Improving Sleep Hygiene
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Behavioral Management of Sleepiness
Common but controversial approaches:
• Drug holidays
• Dietary adjustments
• Nutritional supplements
• Psychotherapy
• Acupuncture
• Exercise
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Psychosocial & Educational Aspects
• Refer to support groups (e.g. Narcolepsy Network)
• National Narcolepsy Registry participation
• Consider psychological impact
• Possible work, school and family interventions
• Medico-legal aspects (e.g. driving, Americans with Disabilities Act, confidentiality)
• Disability benefits
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Conclusions
1. Narcolepsy is a disabling and prevalent disorder
2. The disorder can be reliably and objectively diagnosed
3. Treatment is effective and improves quality of life
4. Our understanding of narcolepsy is rapidly advancing