You're Getting Very Sleepy: Updated Notes on Narcolepsy
You're Getting Very Sleepy: Updated Notes on Narcolepsy Andrea Haller, M.D. Objectives At the end of this talk you should be able to: 1. Describe the basic clinical features of narcolepsy 2. Understand the Diagnostic Criteria and differences between Type 1 and Type 2 Narcolepsy 3. Appreciate that Type 1 Narcolepsy is an autoimmune
disorder 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) Clinical Features 1862: Jean Baptiste Gelineau applied the term narcolepsy to a clinical syndrome of daytime sleepiness with: hypnagogic hallucinations
sleep paralysis cataplexy Narcolepsy: Burden of Disease 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. 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 symptoms 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. 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 dreaming 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 touch 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 cataplexy Cataplexy
Cataplexy 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 obesity 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 hypocretin2/orexin-B) These exert excitatory effects on postsynaptic
neurons through the ox1 and ox2 receptors 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.
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 stems motor inhibitory system causing cataplexy through strong emotional triggers
Hypothalamus Normal: regulates the excitatory system Narcoleptics: have a reduction in hypocretins and therefore a decrease in hypocretin activation which results in sleepiness Hypocretin Pathway Orexin and OxR efferent pathways associated with arousal, vigilance state, and reward pathways. NAc, nucleus accumbens; HA,
thought to be autoexcitatory, project from the lateral HT into these regions to promote wakefulness. 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 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 fluid 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. 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. 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. ICSD-3 Diagnostic Criteria 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: MHC 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 onset 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 populationfrequency 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 symptoms The search for
environmental triggers: Streptococcal infections and ASO antibodies H1N1 subtype of influenza A Pandemrix, monovalent 2009 H1N1 influenza
vaccine Non-HLA, Non-HCRT Genes in Narcolepsy T cell receptor alpha (TCRA): encodes the alpha chain of the mature T cell receptor 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-cells Non-HLA, Non-HCRT Genes in Narcolepsy CPT1B: rate-limiting enzyme in long chain fatty acid 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 response Autoimmune? 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 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
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