1. 2 objectives 1.recognize the clinical presentation of narcolepsy 2.understand the consequences of...

2

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

3

Clinical Presentation of Narcolepsy

• Prevalence

• Level of Disability

• Symptoms

• Consequences

4

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

5

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

6

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

7

TetradPentad

Clinical Presentation: Symptoms

• Excessive daytime sleepiness (EDS)

• Cataplexy• Hypnagogic hallucinations• Sleep paralysis

• Fragmented nocturnal sleep

• Other associated features

8

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

9

Faces of Sleepiness

10

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.”

11

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

12

Quantification of Sleepiness

0

5

10

15

20

25

MSLT MWT Epworth

Sc

ore Normal

Narcoleptic

From Johns 2000

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

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.”

22

• 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

23

• 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.)

24

• Psychosocial problems

• Depression

• Headaches

• Frequent Misdiagnoses – Major depression

– Thyroid disorder

– Chronic fatigue syndrome

– Schizophrenia

Associated Features (cont.)

25

• 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

26

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

27

• 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

28

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

29

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

30

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

31

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

32Courtesy of GJ Lammers

motoneuron

Descending

Inhibiting

Influences

Ia afferent

5 mV 5 ms 5 mV 5 ms

Awake REM

Motoneuron Inhibition

33

Normal and narcoleptic 24-hour PSG recordings

Co

ntr

ol

Un

trea

ted

P

atie

nt

Adapted from Rogers 1994

Sleep / Wake Fragmentation

34

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

35

• 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

36Peter Hjelmström © 1996

A 3-dimensional model of an HLAmolecule with a bound peptide

HLA-DR andHLA-DQ areassociatedwith narcolepsy

HLA and Narcolepsy

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

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

39

• 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

40

• 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

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

42

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

43

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

44

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

45

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

46

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

47

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

48

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

49

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

50

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

51

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

52

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

53

• 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

54

• 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

55

• 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

56

Polysomnographic Findings

57

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

58

R. + L. AT EMG

Central EEG

LOC

ROC

Chin EMG

ECG

HR

VtRIP

Time in seconds

Periodic Limb Movements of Sleep

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

60

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

61

Mean Sleep Latency on MSLT

From Arand et al 2005

0

2

4

6

8

10

12

14

16

18

Narcolepsy IdiopathicHypersomnia


Normals FourNaps

Normals FiveNaps

Sle

ep

La

ten

cy (

Min

ute

s)

62

Central EEG

LOC

Occipital EEG

ROC

Chin EMG

R. + L. AT EMG

HR

ECG

VtRIP

Sleep Onset REM Period

10 seconds

REM

63

SOREMPs in Narcolepsy

• For 2 or more SOREMPs during MSLT:– Sensitivity was 0.79– Specificity was 0.98


64

• 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

65

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

)


66

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

67

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


68

Cerebrospinal Fluid Hypocretin-1 Levels

0

50

100

150

200

250

300

350

400

NarcolepsyWith

Cataplexy

NarcolepsyWithout

Cataplexy

IdiopathicHypersomnia


Controls

CS

F H

yp

oc

reti

n (

pg

/mL

)

From Mignot et al 2002

69

• 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

70

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

71

Therapeutic Approaches

• Pharmacotherapy– Sleepiness

– Cataplexy

– Fragmented nocturnal sleep

– Compliance issues

• Behavioral interventions

• Psychosocial and educational interventions

72

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

73

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

74

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

75

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

76

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

77

Treatment of SleepinessModafinil

Daily Dose Schedule Cost Efficacy Formulation Side Effects

200-800 IV $$$$ + Long +

Methylphenidate


10-150 II $$ +++ Short and Long

++

Dextroamphetamine



++

Methamphetamine



++

78

• 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

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)

*

*

**

*

80

Un

trea

ted

Tre

ated

Adapted from Rogers et al 1994

Reduction of Napping

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

82

-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

83

• Treatment failures– Compliance

– Tolerance

– Other medical, psychiatric or sleep disorders

• Pregnancy and nursing

• Anesthesia

• Recreational drugs

Long-term Management

84

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

85

• 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

86

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


synthesis


synthesis

87

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

88

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

89

• 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

90

• 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

91

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

92

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

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

94

Behavioral Management of Sleepiness

Common but controversial approaches:

• Drug holidays

• Dietary adjustments

• Nutritional supplements

• Psychotherapy

• Acupuncture

• Exercise

95

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

96

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

1. 2 objectives 1.recognize the clinical presentation of narcolepsy 2.understand the consequences of...

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