1. You're Getting Very Sleepy: Updated Notes on Narcolepsy
Andrea Haller, M.D.

2. 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 disorder

3. 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)

4. Clinical Features
1862: Jean Baptiste Gelineau applied the term “narcolepsy” to a clinical syndrome of daytime sleepiness with:
hypnagogic hallucinations
sleep paralysis
cataplexy

5. Narcolepsy: Burden of Disease
Studies on the epidemiology of narcolepsy show an incidence of 0.2 to 1.6 per thousand in European countries, Japan and the United States, a frequency at least as large as that of Multiple Sclerosis.
In many cases, however, diagnosis is not made until many years after the onset of symptoms. This is often due to the fact that patients consult a physician after many years of excessive sleepiness, assuming that sleepiness does not indicate the presence of a disease.
A recent study showed that the mean number of years between the onset of symptoms and correct diagnosis was 14 years. Since the symptoms of narcolepsy usually appear during adolescence, this means that most narcoleptic patients are diagnosed too late to prevent the dramatic impact of the disease on their personal and professional development.

6. 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.
Disabling and underdiagnosed disorder: the effect of narcolepsy on its victims is devastating. Studies have shown that even treated narcoleptic patients are often markedly psychosocially impaired in the area of work, leisure, interpersonal relations, and are more prone to accidents.

7. 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
Cataplexy: intrusion of REM sleep paralysis into wakefulness
hypnagogic hallucinations: In narcolepsy, a person falls asleep quickly with an extremely short REM latency—REM may be at sleep onset. When that happens at night, during the day and if people are waking up from REM (in transitions), in this semi-awake state, they may be dreaming and experience the dreams as reality…frightening and vivid.

8. 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.
Sleep Attack: irresistible and overwhelming urge to sleep. May sleep for several seconds or minutes. In narcolepsy, these periods are times where EDS is much more intense than usual.

9. 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
Hypnagogic hallucinations: In narcolepsy, a person falls asleep quickly with an extremely short REM latency—REM may be at sleep onset. When that happens at night, during the day and if people are waking up from REM (in transitions), in this semi-awake state, they may be dreaming and experience the dreams as reality…frightening and vivid.
Commonly involve seeing things that shift in size and shape
Auditory hallucinations
Person may hallucinate feelings of rubbing or light touch

10. 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
Sleep paralysis: the only muscles that are able to move are the diaphragm and EOM—similar to REM sleep
Again, a disorder of transition, awake with features of REM—intrusion of REM in to wake (similar to cataplexy)

11. 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: Loss of muscle control while awake: slurred speech, slack jaw, knees buckle, total body collapse. Can last few seconds to a few minutes.

12. Cataplexy

13. Cataplexy

14. Daytime sleepiness occurs in all people with narcolepsy, but the frequency of other symptoms varies among individuals. This diagram illustrates the occurrence and overlap of major symptoms in one sample of 100 patients with narcolepsy. In this group, 87% had cataplexy, and about ½ reported hallucinations (hypnagogic or hypnopompic) or sleep paralysis. Only 36% of these individuals had all 4 symptoms. The frequency of symptoms varies among studies and patient populations: for example, cataplexy occurs in 60-80% of patients with narcolepsy in other studies.

15. 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
1. Other sleep disorders: OSA, PLMD/RLS, RSBD
2. Microsleep episodes: A narcolepsy patient can be carrying on a conversation and jump from one unrelated topic to another or just trail off and stop talking altogether. The patient may suddenly perform odd behaviors, such as putting socks in the refrigerator. Their movements may suddenly become slow or clumsy.
3. Automatic behaviors: People can be walking or driving competently but end up in a location different than the intended one.
Evidence suggests that people with narcolepsy are at high risk for obesity compared to the general population. This could be a consequence of low activity level, but research also indicates that deficiencies in the brain peptide hypocretin may play a role in both narcolepsy and eating behaviors, which could increase the risk for obesity.

16. The brain is an organ of up to about 100 billion cells.
The cells of interest in narcolepsy are in the hypothalamus, a small, evolution early ancient an incredibly important structure deep in the brain that helps regulate many of the bodies basic operations including the daily oscillation between sleep and wake.
The cells in question are in the lateral area of the hypothalamus. They number about 30,000 and are the only cells of the brain that produce orexins--a pair of related proteins that were first identified in 1998 and called hypocretins by team of researchers in San Diego for the HT and secretin (a gut hormone with a similar structure), and a couple of weeks later at the University of Texas in mice where the structure was detailed in and they were called orexins.
A litter of Dobermans was the key to figuring out that hypocretins are the major neurotransmitter regulating and modulating sleep.

17. 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 receptors

18. 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
Hypocretin neurons also
1. increase activity in the lateral pontine tegmentum that suppresses REM sleep and
2. project to brain regions that regulate metabolism, motivated behaviors such as award seeking and the autonomic system
Solution phase NMR structure of orexin B based on the PDB coordinates 1CQ0​.

19. 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 triggers
Hypothalamus
Normal: regulates the excitatory system
Narcoleptics: have a reduction in hypocretins and therefore a decrease in hypocretin activation which results in sleepiness

20. 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 OX2 receptor expression; violet, both OX1 and OX2 receptor expression.
Hypocretin neurons, thought to be auto-excitatory, project from the lateral HT into these regions to promote wakefulness.
Locus coeruleus (NE), raphe nuclei (5-HT), and the tuberomammillary body (H), ventral tegmental area (DA)
Anthony L. Gotter, Andrea L. Webber, Paul J. Coleman, John J. Renger and Christopher J. Winrow Pharmacological Reviews July 2012, 64 (3) ; DOI:

21. 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
Across animal models, disrupted hypocretin signaling leads to a narcoleptic phenotype with EDS and cataplexy
Young puppies are particularly susceptible to attacks of cataplexy, they get so excited when they see their master. They collapse in any position with her eyes open, alert, and following any movement. The attacks are reversible by an external stimulus such as petting or calling the animal’s names. In these tests the dogs would be presented with food, they would excitedly run to the food and didn’t have an attack, their hind legs would slump to the floor and down they go. These episodes occur when the dogs see their master, or during intercourse “orgasmolepsy.”

22. Narcolepsy Diagnostic Criteria
The International Classification of Sleep Disorders—Third Edition (ICSD-3), published in February 2014 by the American Academy of Sleep Medicine contained several notable narcolepsy content changes.
Specifically, the terminology has been changed from “narcolepsy with cataplexy” and “narcolepsy without cataplexy” to “narcolepsy type 1” and “narcolepsy type 2.” “This change was made because some patients demonstrate what is considered the fundamental cause for narcolepsy type 1, hypocretin deficiency, but do not [yet] manifest cataplexy.
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.

23. Narcolepsy Type -1
Sleepiness and cataplexy are no longer sufficient to make a diagnosis of narcolepsy. “Now, for narcolepsy type 1, you need sleepiness, cataplexy, and a positive multiple sleep latency test (MSLT)
Another major change is that a sleep onset REM period (SOREMP) on polysomnography the night preceding the MSLT may replace a SOREMP on the MSLT. “Sleepiness and low CSF-hypocretin-1 concentrations, regardless of cataplexy status, are also now sufficient to diagnose narcolepsy type 1
So, if a person the night before goes into REM sleep within 15 minutes of sleep onset at the beginning of the night and then on the MSLT the following day has a sleep onset REM period on only one of the four or five naps, that is adequate in the correct clinical setting to call it narcolepsy
Also provides an updated definition of cataplexy in children. In children, appearance of cataplexy is often atypical, without triggers and affecting the face (eg, mouth opening, tongue protrusion). This occurs often with very abrupt sleepiness and weight gain.
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.

24. 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.

25. ICSD-3 Diagnostic Criteria
1. Hypocretin determination is not a requirement for diagnosis
2. A SOREMP during a night PSG is narcolepsy unless proven otherwise
3. A patient can move from type 2 to type 1 if they develop cataplexy

26. 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
There is now overwhelming evidence that by far the most common cause of narcolepsy is an autoimmune attack, where the body’s immune system mishandles an upper respiratory infection and mistakenly wipes out the estimated 30,000 hypocretin producing neurons in the lateral hypothalamus.

27. 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
Familial Incidence: This still suggests some genetic predisposition as this is still fold greater than in the general population.
2. Among 21 published case-reports of monozygotic twins, only 25% were concordant for narcolepsy-cataplexy (32% concordance when narcolepsy either with or without cataplexy was considered).1

28. 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 symptoms
The identification of the tight association with DR2/ DQB1*06:02 immediately suggested an autoimmune mechanism for narcolepsy, which is also consistent with the peripubertal pattern of onset, and low rates of concordance in monozygotic twins.

29. The search for environmental triggers:
Streptococcal infections and ASO antibodies
H1N1 subtype of influenza A
Pandemrix, monovalent 2009 H1N1 influenza vaccine
1. Recent studies indicate that upper airway infections may be key players. Studies repeatedly suggest a role for Streptococcal infections, and increased levels of streptococcal antibodies (anti-streptolysin O) have been noted in patients compared to age-matched Caucasian controls when analyzing serum samples taken within 3 years of narcolepsy onset. This association then dissipates when studying samples from cases with longstanding disease.
2. Exposure to antigens from H1N1 subtype of influenza A virus may also trigger the disease. An apparent increase in recent onset narcolepsy cases was noted in major narcolepsy centers in France, Canada and the US following the 2009 H1N1 swine flu pandemic.
3. In addition, an increased risk was found following vaccination with Pandemrix, a monovalent 2009 H1N1 influenza vaccine that was used in several European countries during the H1N1 influenza pandemic.

30. 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-cells
The T cell receptor alpha (TCRA) is now established as a significant and general susceptibility factor for narcolepsy, based on multiple replications and remarkably consistent odds ratios across studies. Three SNPs within the TCRA locus were found to be significantly associated with narcolepsy.
The TCRA locus is an obvious biological candidate, as it 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, and following engagement with the antigen-MHC complex, initiates an immune response.
Together the HLA and T cell receptor associations clearly demonstrate an autoimmune basis for narcolepsy, as unlike HLA, functional TCRs are only expressed in immune T-cells.
The binding and presentation of processed antigens by HLA proteins is critical to the development of tolerance in the thymus (by deletion of self-reactive T cells) and to determination of an immune response in the periphery, and not surprisingly, the vast majority of autoimmune diseases have shown associations with HLA variants.

31. 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 response
The T cell receptor alpha (TCRA) is now established as a significant and general susceptibility factor for narcolepsy, based on multiple replications and remarkably consistent odds ratios across studies. Three SNPs within the TCRA locus were found to be significantly associated with narcolepsy.
The TCRA locus is an obvious biological candidate, as it 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, and following engagement with the antigen-MHC complex, initiates an immune response.
Together the HLA and T cell receptor associations clearly demonstrate an autoimmune basis for narcolepsy, as unlike HLA, functional TCRs are only expressed in immune T-cells.

32. 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.
Some clinical features of narcolepsy are less typical of autoimmune disorders
Tribbles 2 Antibodies: It is not clear how these antibodies relate to the disease process, as there is no direct evidence that the antibodies injure hypocretin neurons, and TRIB2 expression is widespread in the brain and other tissues.

33. 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