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You're Getting Very Sleepy:
You're Getting Very Sleepy:

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You're Getting Very Sleepy:Updated Notes on Narcolepsy

Andrea Haller, M.D.Slide2



At the end of this talk you should be able to:


Describe the basic clinical features of narcolepsy

Understand the Diagnostic Criteria and differences between Type 1 and Type 2 Narcolepsy

Appreciate that Type 1 Narcolepsy is an autoimmune disorderSlide3


A central nervous system disorder that is an important cause of persistent and excessive sleepiness

The second most common cause of disabling daytime sleepiness after sleep apnea.

From: “Deuce


, Male Gigolo” (1999)Slide4

Clinical Features

1862: Jean Baptiste


applied the term “narcolepsy” to a clinical syndrome of daytime sleepiness with:

hypnagogic hallucinations

sleep paralysis


Narcolepsy: Burden of DiseaseSlide6

Narcolepsy: Epidemiology

Equal prevalence in men and women

Typically begins in teens and early twenties, but can occur as early as age 5 or after age 40

Symptoms may worsen over the first few years and then persist for life

Half of all patients report that symptoms interfere with job, marriage, or social life.Slide7


Can be considered a disorder of state control

Elements of sleep intrude into wakefulness and elements of wakefulness intrude into sleep

This state instability results in characteristic symptomsSlide8

Excessive daytime sleepiness

All patients with narcolepsy have excessive daytime sleepiness

Over 24 hours, they do not sleep more than normal controls, but they are prone to fall asleep throughout the day, often at inappropriate times.

“Sleep attacks”

Often improved temporarily by a brief nap

Patients with untreated narcolepsy have an ESS score greater than 15.Slide9

Associated Features:Hypnagogic hallucinations

Vivid, often frightening hallucinations that occur just as the patient is falling asleep

Can be visual, auditory or tactile sensations


: occur upon awakening

Likely result from wakefulness during REM sleep dreamingSlide10

Associated Features:Sleep paralysis

Complete inability to move a minute or two after awakening

Episodes may be accompanied by hypnagogic hallucinations.

Can be ended by falling back to sleep or by sensory stimulation such as a touchSlide11

Associated Features:Cataplexy

Sudden episodes of bilateral muscle weakness leading to partial or complete collapse

Most often triggered by strong emotions such as laughter, anger or excitement

Can also be triggered by a large meal, periods of stress

Typical episodes last one to two minutes, and are not associated with impairment of consciousness

Between 60-80% of narcoleptic individuals develop cataplexySlide12



Other symptoms…

Sleep maintenance insomnia

Microsleep episodes

Automatic behaviors

Fragmented nighttime sleep

Higher than expected incidence of other sleep disorders

Slightly higher incidence of adult onset diabetes mellitus, migraine headaches and obesitySlide16


Narcolepsy type 1 is the result of a selective loss of a small population of neurons in the lateral hypothalamus.

These neurons synthesize hypocretin peptides (hypocretin-1/orexin-A and hypocretin-2/orexin-B)

These exert excitatory effects on postsynaptic neurons through the ox1 and ox2 receptorsSlide18

Hypocretins (orexins)

The hypocretins are


released during wakefulness

Increase the activity of many brain regions involved in the promotion of wakefulness

Locus coeruleus (NE), raphe nuclei (5-HT), and the tuberomammillary body (H), ventral tegmental area (DA)

Help stabilize wakefulness, preventing inappropriate transitions into REM or non-REM sleep

Solution phase


structure of orexin B based on the


coordinates 1CQ0​.Slide19

Neurological Correlates

Dorsolateral Pons and Medial Medulla:

Normal: suppresses muscle tone during REM

Narcoleptics: causes cataplexy


Normal: aids perception of emotional responses

Narcoleptics: activates brain stem’s motor inhibitory system causing cataplexy through strong emotional triggersHypothalamusNormal: regulates the excitatory systemNarcoleptics: have a reduction in hypocretins and therefore a decrease in hypocretin activation which results in sleepinessSlide20

Hypocretin Pathway

Orexin and


efferent pathways associated with arousal, vigilance state, and reward pathways.


, nucleus

accumbens; HA, histaminergic; DA, dopaminergic; ACh, cholinergic; NE, noradrenergic; 5-HT, serotonergic. Green, orexinergic neuron projections; red, preferential OX1 receptor expression; blue, preferential OX


receptor expression; violet, both OX


and OX


receptor expression.

Anthony L.


, Andrea L. Webber, Paul J. Coleman, John J.


and Christopher J.


Pharmacological Reviews July 2012, 64 (3) 389-420; DOI:

Hypocretin neurons, thought to be auto-excitatory, project from the lateral HT into these regions to promote wakefulness. Slide21


Animal models first identified the importance of hypocretin in narcolepsy (dogs, mice)

People with narcolepsy also have hypocretin deficiency

About 90% of narcoleptics with cataplexy (Type 1) have little or no detectable orexin in their spinal fluidSlide22

Narcolepsy Diagnostic Criteria

1 American Academy of Sleep Medicine. Central disorders of


. In: The International Classification of Sleep Disorders, 3rd Edition (ICSD-3). Darien, IL: American Academy of Sleep Medicine; 2014.Slide23

Narcolepsy Type -1

1 American Academy of Sleep Medicine. Central disorders of


. In: The International Classification of Sleep Disorders, 3rd Edition (ICSD-3). Darien, IL: American Academy of Sleep Medicine; 2014.Slide24

Narcolepsy Type -2

1 American Academy of Sleep Medicine. Central disorders of


. In: The International Classification of Sleep Disorders, 3rd Edition (ICSD-3). Darien, IL: American Academy of Sleep Medicine; 2014.Slide25

ICSD-3 Diagnostic CriteriaSlide26


Autoimmune process likely mediates the selective destruction of hypothalamic hypocretin neurons in narcolepsy type 1.

Rare family cases

Discordance in monozygotic twins

Young and bimodal age at onset

Importance of genetic background: MHCSlide27

Pathophysiology: Autoimmune Process

Primarily a sporadic disorder

Estimates of familial incidence are low: 4.3% of all cases in Canada to 9.9% in Japan. The risk of a first-degree relative of a patient having narcolepsy-cataplexy is 1-2%.

Twin studies: Most monozygotic twin pairs are discordant for narcolepsy suggesting that nongenetic, and even environmental factors may also be involved in the pathophysiology

Young and bimodal age at onsetSlide28

Autoimmune Process: Major


Locus (MHC)

DQB1*06:02 is the most important factor predisposing to narcolepsy type 1

>98% of patients with narcolepsy type 1 carry HLA class II HLA-DQB1*06:02 allele.

Still, common in the population—frequency varies across ethnic groups from 12% in Japanese) to 38% in African Americans

Not sufficient for the development of the disease.Homozygotes have additional 2-4 fold risk for narcolepsy compared to heterozygotes, and may also exhibit more severe symptomsSlide29

The search for environmental triggers:

Streptococcal infections and ASO antibodies

H1N1 subtype of influenza A


, monovalent 2009 H1N1 influenza vaccine Slide30

Non-HLA, Non-HCRT Genes in Narcolepsy

T cell receptor alpha (TCRA):

encodes the alpha chain of the mature T cell receptor αβ heterodimer

this protein is localized on the surface of T cells and recognizes antigens bound and presented by class I or class II MHC molecules

following engagement with the antigen-MHC complex, initiates an immune response

functional TCRs are only expressed in immune T-cellsSlide31

Non-HLA, Non-HCRT Genes in Narcolepsy

CPT1B: rate-limiting enzyme in long chain fatty acid β oxidation in muscle mitochondria, a pathway implicated in regulation of theta frequency in REM sleep in mouse models

CHKB is a kinase involved in phosphatidylcholine synthesis- a precursor to acetylcholine which is a known regulator of REM sleep and wakefulness.

P2RY11 purinergic receptor gene (a susceptibility locus), appear to play a role in modulating the immune responseSlide32

In narcolepsy, females are not at increased risk

It has been difficult to find direct evidence of humoral or cellular autoimmune attack

Recent identification of reactive autoantibodies against the Tribbles 2 homolog (TRIB2) protein in sera of narcolepsy cases.


Secondary Narcolepsy: structural lesions

Structural lesions of the


and brainstem have resulted in a similar syndrome, although patients usually lack the full narcolepsy syndrome



Ischemia (strokes)

Vascular malformations

Patients are likely to have other focal neurologic signs and symptoms

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You're Getting Very Sleepy: - Description

Updated Notes on Narcolepsy Andrea Haller MD Objectives   At the end of this talk you should be able to   Describe the basic clinical features of narcolepsy Understand the Diagnostic Criteria and differences between Type 1 and Type 2 Narcolepsy ID: 687411 Download Presentation

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