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
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Slide1
You're Getting Very Sleepy:Updated Notes on Narcolepsy
Andrea Haller, M.D.Slide2
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
Appreciate that Type 1 Narcolepsy is an autoimmune disorderSlide3
Narcolepsy
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
Bigalow
, Male Gigolo” (1999)Slide4
Clinical Features
1862: Jean Baptiste
Gelineau
applied the term “narcolepsy” to a clinical syndrome of daytime sleepiness with:
hypnagogic hallucinations
sleep paralysis
cataplexySlide5
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
Narcolepsy
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
Hypnopompic
: 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
CataplexySlide13
CataplexySlide14Slide15
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 obesitySlide16Slide17
Pathophysiology
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
synaptically
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
NMR
structure of orexin B based on the
PDB
coordinates 1CQ0.Slide19
Neurological Correlates
Dorsolateral Pons and Medial Medulla:
Normal: suppresses muscle tone during REM
Narcoleptics: causes cataplexy
Amygdala
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
OxR
efferent pathways associated with arousal, vigilance state, and reward pathways.
NAc
, 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
2
receptor expression; violet, both OX
1
and OX
2
receptor expression.
Anthony L.
Gotter
, Andrea L. Webber, Paul J. Coleman, John J.
Renger
and Christopher J.
Winrow
Pharmacological Reviews July 2012, 64 (3) 389-420; DOI: https://doi.org/10.1124/pr.111.005546
Hypocretin neurons, thought to be auto-excitatory, project from the lateral HT into these regions to promote wakefulness. Slide21
Neurobiology
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
hypersomnolence
. 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
hypersomnolence
. 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
hypersomnolence
. In: The International Classification of Sleep Disorders, 3rd Edition (ICSD-3). Darien, IL: American Academy of Sleep Medicine; 2014.Slide25
ICSD-3 Diagnostic CriteriaSlide26
Pathophysiology
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
Histocompatability
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
Pandemrix
, 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.
Autoimmune?Slide33
Secondary Narcolepsy: structural lesions
Structural lesions of the
hypothalamus
and brainstem have resulted in a similar syndrome, although patients usually lack the full narcolepsy syndrome
Tumors
Demyelination
Ischemia (strokes)
Vascular malformations
Patients are likely to have other focal neurologic signs and symptoms