1
Objectives
1. Recognize the clinical presentation of
narcolepsy
2. Understand the consequences of narcolepsy
3. Learn about our evolving understanding of
narcolepsy
4. Explore the pathophysiology of narcolepsy
5. Review standard diagnostic criteria for
narcolepsy
6. Compare current treatments for narcolepsy
and discuss possible future treatments
2
Clinical Presentation of Narcolepsy
•
•
•
•
Prevalence
Level of Disability
Symptoms
Consequences
3
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
4
Narcolepsy With Cataplexy:
Prevalence
Percentage of Population
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Israel
Data from Mignot, 1998
Finland
Northern
California
Southern
California
Japan
Multiple
Sclerosis
(US)
5
SF-36 Scores
Quality of Life in Narcolepsy
100
90
80
70
60
Narcoleptics
50
40
Multiple
Sclerosis
30
20
Parkinson's
Disease
10
0
Post Partum
Depression
Physical
Role
Bodily Pain
Functioning Limitations
Due to
Physical
Problems
General
Health
Vitality
Social
Role
Functioning Limitations
Due to
Emotional
Problems
Data From Da Costa et al 2005, Riazi et al 2003 and Beusterien et al 1999
Mental
Health
Controls
6
Clinical Presentation: Symptoms
• Excessive daytime
sleepiness (EDS)
• Cataplexy
• Hypnagogic hallucinations
• Sleep paralysis
Tetrad
Pentad
• Fragmented nocturnal sleep
• Other associated features
7
Symptom Prevalence
100
90
From
ICSD-2
except
cataplexy
estimate
from
AnicLabat et
al 1999
Percentage of Patients
80
70
60
50
40
30
20
10
0
Sleepiness
Hypnagogic Sleep Paralysis
Hallucinations
Disrupted
Sleep
Cataplexy
8
Faces of Sleepiness
9
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.”
10
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
11
Quantification of Sleepiness
25
20
Score
15
Normal
Narcoleptic
10
5
0
MSLT
MWT
Epworth
From Johns 2000
12
Sleepiness While Driving
Do you drive?
Fall asleep driving
Cataplexy driving
Sleep paralysis driving
Frequent near accidents
Led to accidents
Higher insurance
Suspended license
From Broughton et al 1981
Narcolepsy
48%
66
29
12
67
37
16
7
Controls
63%
6
0
0
0
5
1
4
13
Percentage of Obstacles Hit in
Driving Simulator
Driving Simulator Errors
10
9
8
7
6
5
4
3
2
1
0
Controls
EDS, No Narcolepsy
Narcolepsy
Adapted from Findley, 1995
14
Percentage of Patients
Percentage of Patients with Sleep
Related Motor Vehicle Accidents
60
50
40
30
20
10
0
Men
Women
*
*
Obstructive
Sleep Apnea
Data from Aldrich, 1989
Narcolepsy
*
Other
Sleepiness
Control
*Significantly different from Controls
15
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
16
Performance Deficits
Wilkinson Addition
Test
Digit Symbol Substitution
Test
800
100
700
90
600
80
70
500
60
400
50
300
10:00 AM
12 noon
2:00 PM
4:00 PM
6:00 PM
10:00 AM
12 noon
2:00 PM
4:00 PM
6:00 PM
Control
Narcoleptic
Adapted from Mitler et al 1982
17
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
18
Triggers for Cataplexy
100
Percentage of Patients
90
80
70
60
50
40
30
20
10
0
Laughing
Adapted from Anic-Labat 1999
Joking
Anger
Stress
Sex
19
Percentage of Patients
Muscles Affected by Cataplexy
120
100
80
60
40
20
0
Legs / knees
Adapted from Anic-Labat 1999
Jaw
Slurred speech
Generalized
(falling to
ground)
20
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.”
21
Associated Features
• Sleep paralysis
– Sudden inability to move on falling
asleep or on awakening
– Episodes are generally brief and benign,
end spontaneously
– Can cause significant anxiety
22
Associated Features (cont.)
• 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
23
Associated Features (cont.)
• Psychosocial problems
• Depression
• Headaches
• Frequent Misdiagnoses
– Major depression
– Thyroid disorder
– Chronic fatigue syndrome
– Schizophrenia
24
Headaches May Be Common In Narcolepsy
• 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)
25
Age of Onset of Symptoms
Percentage of
Patients
25
20
15
10
5
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
Age
Data from Parkes 1985
26
Prepubertal Narcolepsy
• 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
27
Narcolepsy Time Line
Hypocretin in animals, 1998
Amphetamines
used for
treatment,
1935
1880
1900
Canine narcolepsy, 1973
1920
1940
1960
1980
2000
Sleep Onset REM Period, 1960
Syndrome first
described, 1877
HLA association, 1981
Hypocretin in
humans, 2000
28
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
29
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
30
Narcolepsy Is Characterized By Sudden
Transitions From Wakefulness To REM Sleep
Central EEG
Occipital EEG
LOC
ROC
Chin EMG
R. + L. AT EMG
ECG
Rapid Eye Movements
Decreased chin muscle tone
HR
VtRIP
31
Motoneuron Inhibition
Awake
5 mV
5 ms 5 mV
REM
5 ms
Descending
Inhibiting
Influences
Ia afferent
 motoneuron
Courtesy of GJ Lammers
32
Untreated
Patient
Control
Sleep / Wake Fragmentation
Normal and narcoleptic 24-hour PSG recordings
Adapted from Rogers 1994
33
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
34
HLA-Narcolepsy Association
• 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
35
HLA and Narcolepsy
HLA-DR and
HLA-DQ are
associated
with narcolepsy
A 3-dimensional model of an HLA
molecule with a bound peptide
Peter Hjelmström © 1996
36
Genetic Factors in Narcolepsy
•
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 nonHLA gene may confer
narcoleptic susceptibility
A 3-dimensional model of an HLA
molecule with a bound peptide
Peter Hjelmström © 1996
37
Percentage of patients with DQB1*0602
HLA DQB1*0602 Association
100
90
80
70
60
50
40
30
20
10
0
Narcolepsy
Narcolepsy With
Without Cataplexy
Cataplexy
Data from Mignot et al 2002
Idiopathic
Hypersomnia
Control
38
Potential Roles of HLA
• 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
39
Environmental and Developmental Factors
• 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)
40
Pathophysiology
Animal Models
• Canine Narcolepsy
– Cataplexy
– REM onset
– Sleepiness
– Drug response
• Murine Narcolepsy
– Cataplexy
– REM sleep onset
Reprinted from Cell, Vol. 98(3) Copyright © 1999, with permission from Elsevier Science.
41
Animal Models
12q13-21
•
Defects in the hypocretin /
orexin system are
responsible for narcolepsy
in animal models
•
Canine narcolepsy gene
Hcrtr2
– Hypocretin receptor 2
(Hcrtr2)
•
Mouse narcolepsy
– Deletion of hypocretin
peptide genes
42
Hypocretin System
Arcuate
NPY
Inputs
Other Peptides:
CRF, CCK, MCH, etc
Locus
Coeruleus
Hypocretin
Containing
Cells of the
Lateral
Hypothalamus
Cortex
Layer
VIb
Laterodorsal
Tegmental
Nucleus
From de Lecea and Sutcliffe, 2005
43
Hypocretin Cell Loss in Human
Narcolepsy
Normal
90000
80000
70000
Narcolepsy
Number of Neurons
60000
50000
40000
30000
20000
10000
0
Narcolepsy
Normal
Photomicrographs courtesy J Siegel, UCLA, 2000
Data from Thannickal et al 2000
44
Neuroanatomy
Hypothalamus:
Integration of
sleep and
circadian
influences
Pons:
REM sleep
generator
Thalamocortical
Loops:
EEG
synchronization
Amygdala &
Limbic System:
Emotional
triggering of
cataplexy
Spinal Cord
Motoneurons:
REM sleep atonia,
cataplexy
45
Neurotransmitters
Cortex:
Ach, Dopamine
Basal
Forebrain:
Ach, Adenosine
Posterior
Hypothalamus:
Hypocretin
Amygdala &
Limbic
System:
Ach, Dopamine
Brainstem:
Ach cell group
Monoamine cell groups
Spinal Cord:
Glycine
46
Hypothalamic Regulation of Sleep
SLEEP
WAKE
HYPOCRETIN
CONTAINING
NEURONS
VENTROLATERAL
PREOPTIC
NUCLEUS
LATERAL
HYPOTHALAMU
S
SUBPARAVENTRICULAR
SUPRACHIASMATI
C
NUCLEUS
After Saper et al 2005
CLOCK INFORMATION
ZONE
DORSOMEDIAL
NUCLEUS OF THE
HYPOTHALAMUS
47
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
48
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
49
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
50
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
51
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
52
Clinician’s Assessment of EDS
• 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
53
Criteria for Cataplexy
•
•
•
•
•
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
54
Polysomnographic Findings
• 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
55
Polysomnographic Findings
56
Limb Movement Index
(2nd Night)
Frequency of Periodic Limb
Movements in Sleep Disorders
25
20
15
10
5
0
Narcolepsy
Data from Hornyak et al 2005
Sleep Apnea
Insomnia
57
Periodic Limb Movements of Sleep
Central EEG
LOC
ROC
Chin EMG
R. + L. AT EMG
ECG
HR
VtRIP
Time in seconds
58
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
59
MSLT Practice Parameters
The 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
60
Mean Sleep Latency on MSLT
18
16
Sleep Latency (Minutes)
14
12
10
8
6
4
2
0
Narcolepsy
From Arand et al 2005
Idiopathic
Hypersomnia
Obstructive
Sleep Apnea
Normals Four
Naps
Normals Five
Naps
61
Sleep Onset REM Period
Central EEG
Occipital EEG
LOC
ROC
REM
Chin EMG
R. + L. AT EMG
ECG
HR
10 seconds
VtRIP
62
SOREMPs in Narcolepsy
• For 2 or more SOREMPs during MSLT:
– Sensitivity was 0.79
– Specificity was 0.98
From Arand et al 2005
63
Factors Affecting MSLT
• Sleep disruption and other sleep disorders
• Sleep deprivation / extension
• Circadian factors / shift work
• Age-related effects
• Hypnotic agents / alcohol
• Stimulants / caffeinated substances
• Psychological stimulation
64
Effect of Age on MSLT Latency in Normal Subjects
Mean Latency (Minutes)
17
16
15
14
13
12
11
10
9
8
10
20
30
40
50
60
70
80
Age
From Arand et al 2005
65
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
66
Effects of Age on MWT in Normals
40 Minute Protocol
20 Minute Protocol
Mean Latency (Minutes)
40
35
30
25
20
15
10
30-39
40-49
50-59
60-69
Age
From Arand et al 2005
67
Cerebrospinal Fluid Hypocretin-1
Levels
400
CSF Hypocretin (pg/mL)
350
300
250
200
150
100
50
0
Narcolepsy
With
Cataplexy
From Mignot et al 2002
Narcolepsy
Without
Cataplexy
Idiopathic
Obstructive
Hypersomnia Sleep Apnea
Controls
68
ICSD-2 Diagnostic Criteria
• 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
69
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
70
Therapeutic Approaches
• Pharmacotherapy
– Sleepiness
– Cataplexy
– Fragmented nocturnal sleep
– Compliance issues
• Behavioral interventions
• Psychosocial and educational interventions
71
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
72
Action of Stimulants
Presynaptic
Postsynaptic
dopa
dopamine
GHB reduces cell firing but
does not inhibit dopamine
synthesis
U
U
tyramine
U
U
Methylphenidate and
possibly modafinil
Block re-uptake
Amphetamine-like stimulants
inhibit VMAT, increase
dopamine release
73
Potential Wake-Promoting
Systems
Neurotransmitters
– Dopamine
– Histamine
– Hypocretins
See Mignot et al 2002 for review
Pharmaceutical Agents
– Amphetamine-like
compounds
– H3 receptor agonists
– Hypocretin agonists
– Sodium oxybate
74
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
75
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
76
Treatment of Sleepiness
Modafinil
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
++
77
Initiating Therapy for Sleepiness
•
•
•
•
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
78
Reduction of Sleepiness -Modafinil
18
16
14
* *
12
Placebo
10
* *
8
6
Modafinil
200 mg
*
4
Modafinil
400 mg
2
0
MSLT
MWT
Epworth
*Significantly different from
placebo (p< 0.05)
Adapted from US Modafinil in Narcolepsy Multicenter Study Group 2000.
79
Treated
Reduction of Napping
Adapted from Rogers et al 1994
80
Pharmacotherapy: Relative Efficacy
100
Baseline
90
Treatment
Percent of Normal
80
70
60
50
40
30
20
10
al
N
or
m
lp
h
et
hy
M
tr
oa
m
ph
e
en
i
ta
m
da
t
in
e
fin
od
a
M
D
ex
Adapted from Mitler et al1991
e
il
H
B
G
C
od
ei
ne
0
81
Quality of Life
SF-36 Change in Score
25
*
20
15
Placebo (n=163)
Modafinil 200 mg
Modafinil 400mg
*
*
*
10
*
*
5
0
-5
Physical
Role
Bodily pain
functioning limitationsphysical
General
Health
Vitality
Social
function
Role
limitationemotional
Mental
health
*p<0.05 between treatment group and placebo
Adapted from Beusterien et al 1999
82
Long-term Management
• Treatment failures
– Compliance
– Tolerance
– Other medical, psychiatric or sleep disorders
• Pregnancy and nursing
• Anesthesia
• Recreational drugs
83
Percentage of Patients
Compliance With Stimulant
Medication
100
80
60
40
20
0
Full Amount Between 80 Between 50
and 99%
and 80%
Less Than
50%
Portion of Prescribed Dose Taken
Adapted from Rogers et al 1997
84
Cataplexy and Disassociated REM
Sleep Features
• Tricyclic
antidepressants
– Protriptyline (10 to 60 mg/day)
– Clomipramine / Imipramine
(25 to 150 mg/day)
– Anti-cholinergic side effects
• Sodium oxybate
– 3-9 g/night
• Miscellaneous treatments
– Venlafaxine (75 to 150 mg/day)
– Reboxetine (not available in US)
• Selective serotonin reuptake inhibitors
– Fluoxetine / Paroxetine (20 to
60 mg/day)
– Better tolerated but higher
dose often needed
85
Protriptyline, imipramine
and desipramine
Block NE re-uptake
Postsynaptic
U
Presynaptic
U
norepinephrine
serotonin
GHB reduces cell firing but
does not inhibit dopamine
synthesis
U
U
dopamine
Clomipramine, fluoxetine
Block serotonin re-uptake
86
Cataplexy Treatment -- Protriptyline
Cataplexy Severity Scale
25
20
15
10
5
0
Baseline
10 mg
30 mg
Dose
Adapted from Mitler et al 1990
87
Episodes of Cataplexy Per
Week
Cataplexy Treatment – GHB
35
30
25
20
15
10
5
0
Placebo
Data from Xyrem International Study Group 2005
4.5 g
6g
9g
88
Treatment of Cataplexy
• 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
89
Fragmented Nocturnal Sleep
• 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
90
Compliance
Always ask your patients
“Are you having any difficulties taking your medication?”
• 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
91
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
92
Napping and Improving Sleep Hygiene
Reduction of Unplanned
Naps (minutes/day)
40
Very sleepy
30
20
10
Moderately sleepy
0
-10
Least sleepy
-20
Severity Group
Adapted from Rogers et al 2001
93
Behavioral Management of Sleepiness
Common but controversial approaches:
• Drug holidays
• Dietary adjustments
• Nutritional supplements
• Psychotherapy
• Acupuncture
• Exercise
94
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
95
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
96