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Narcolepsy Robert Rieti D.O., FCCP

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1 Narcolepsy Robert Rieti D.O., FCCP
The Nightmare is a 1781 oil painting by Anglo- Swiss artist Henry Fuseli (1741–1825). Since its creation, it has remained Fuseli's best-known work. With its first exhibition in 1782 at the Royal Academy of London, the image became famous; an engraved version was widely distributed and the painting was parodied in political satire. Due to its fame, Fuseli painted at least three other versions of the painting. Thought to be one of the classic depictions of sleep paralysis as a demonic visitation. Interpretations of The Nightmare have varied widely. The canvas seems to portray simultaneously a dreaming woman and the content of her nightmare. The incubus and the horse's head refer to contemporary belief and folklore about nightmares, but have been ascribed more specific meanings by some theorists.[1] Contemporary critics were taken aback by the overt sexuality of the painting, which has since been interpreted by some scholars as anticipating Freudian ideas about the unconscious. Robert Rieti D.O., FCCP

2 Overview Epidemiology Etiology History Prevalence Age of onset
Orexin/hypocretin Genetic factors Autoimmune hypothesis Secondary narcolepsy

3 Overview Clinical features Diagnostic evaluation/criteria
Excessive daytime sleepiness(EDS) Cataplexy Hypnagogic hallucinations Sleep paralysis Diagnostic evaluation/criteria Differential diagnosis

4 Overview Treatment of Narcolepsy Nonpharmacologic therapy
Modafinil Methylphenidate Amphetamines REM suppressing agents Sodium oxybate Pitolisant?

5 History 1877 First description in the medical literature
1880 Gelineau called the disorder “narcolepsy” 1902 Loewenfeld coined the term “cataplexy” 1935 First use of amphetamines in the treatment of narcolepsy 1960 Description of Sleep Onset REM periods in a narcoleptic subject 1970 Description of the Multiple Latency Test 1973 First report of a narcoleptic dog 1983 Association of narcolepsy with HLA-DR2 1985 Monoaminergic and cholinergic imbalance in narcolepsy 1992 Association of narcolepsy with HLA-DQB1*0602 1998 Identification of hypocretins/orexins and their receptors 1999 Hypocretin mutations cause narcolepsy in mice and dogs 2000 Narcolepsy is also associated with an hypocretin deficiency 2013 CD4 T cell cross-reactivity to H1N1

6 Prevalence Narcolepsy type 1(with cataplexy) = per 100,000 people Narcolepsy type 2(without cataplexy) ~ 20-34per 100,000 people Estimated 1 in 20 of US Sleep Clinic patients ~ twice as common as multiple sclerosis ~ half as common as Parkinson’s disease Equally common in men and women 1 in 2 are estimated to be undiagnosed

7 Age of Onset - Most common age of onset is adolescence.
Okun, et al., SLEEP, Vol. 25, No. 1, 2002 Age of onset, cataplexy, hypnagogic hallucinations, and sleep paralysis in 469, 438, 210, and 189 patients, respectively. - Most common age of onset is adolescence. - A second peak occurs near 40 years of age. Okun, et al., SLEEP, Vol. 25, No. 1, 2002

8 Etiology Hypocretin/orexin
Released from neurons in the lateral hypothalamus during wakefulness Increase activity in locus coeruleus, raphe nuclei, and tuberomammillary nucleus Stabilize wakefulness and prevent inappropriate transitions into REM and NREM sleep Narcolepsy results from a loss of these neuropeptides


10 Crocker, et al 2005; Peyron, et al 2000; Thannickal, et al 2000.
The number of hypocretin-producing neurons in the brain is markedly reduced in people with narcolepsy with cataplexy. These diagrams show the hypothalamus in a coronal plane in control and narcolepsy subjects. The number of hypocretin neurons (black dots) is much fewer in the brain of a person with narcolepsy with cataplexy. People with narcolepsy with cataplexy have a roughly 90% reductions in the number of hypothalamic neurons producing hypocretin/orexin with little or no hypocretin-1 in their spinal fluid. Crocker, et al 2005; Peyron, et al 2000; Thannickal, et al 2000.

11 Genetic Factors Narcolepsy usually occurs sporadically, but genetic factors play an important role Familial disease is uncommon, 4% of patients have an affected relative Risk of narcolepsy in 1st degree relatives is 6-18 times that of unrelated individuals Only 25% of monozygotic twins share narcolepsy

12 DQB1*0602 haplotype (DR2) High correlation between narcolepsy and this class II antigen of the major histocompatibilty complex Present in 95% of patients with catplexy and 96% of those with hypocretin/orexin deficiency One of the highest HLA disease associations in all of medicine 1st degree relatives have a 40-fold increased risk

13 Testing for DQB1*0602 haplotype (DR2)
Limited benefit to testing HLA-DR2 Most people positive for the antigen do not develop narcolepsy Antigen-negative cases have been reported Narcoleptics without cataplexy are less likely to be antigen positive

14 Autoimmune hypothesis
Narcolepsy is strongly associated with HLA haplotypes → T cell-mediated process Patients with narcolepsy(type 1) have populations of T-cells that react with fragments of hypocretin-1 Humeral mechanism is also possible → antibodies against tribbles homolog 2 increased after the onset of narcolepsy Neurodegenerative process → number of astrocytes are modereately increased in the hypocretin region

15 Higher anti-streptolysin O titers 1-3 years after narcolepsy onset
Aran, et al, 2009

16 ● Narcolepsy patients have high levels of antibodies against Trib2
● Tribbles homolog 2 is expressed in hypocretin neurons ● Titers of narcolepsy patients remain elevated ELISA determination of Trib2-specific antibodies in sera. (A) Each symbol corresponds to the serum of a single subject. Mean ± 1 SD of each group is shown next to the individual values. The dotted horizontal line indicates the mean Trib2-specific antibody titer in healthy control subjects plus 2 SD. All values are relative to the optical density of a healthy control subject (which is equal to 1). P values correspond to independent t-tests between indicated groups. OIND, other inflammatory neurological diseases. (B) Mean ± 1 SD of Trib2-specific antibody titers at different intervals from the disease onset. The solid line and dotted lines indicate mean titer ± 1 SD in normal control subjects. Numbers indicate the number of narcolepsy patients at each interval. Note the sharp decrease in titers within the first 2–3 years, reaching normal values. From 5 up to 30 years after disease onset, the titers of narcolepsy patients remain stable but significantly (1 SD, P < 5 × 10–5) higher than those of healthy control subjects (n = 42).

17 Narcolepsy after receiving Pandemrix
Pandemrix was used in certain countries during the 2009 to 2010 H1N1 influenza pandemic, but it was not used in the United States. In early investigations, vaccinated children and adolescents in Finland and Sweden had a four to nine fold increased risk of narcolepsy compared with unvaccinated children and adolescents The risk appears to be greatest in children and adolescents with DQB1*0602.

18 Secondary narcolepsy Seen with lesions of the posterior and lateral hypothalamus or midbrain Lesions are usually caused by tumors, strokes demylination, or inflammation Patients develop hypersomnia and overt neurologic deficits (e.g. abnormal eye movements, focal weakness, pitutary dysfunction, or obesity) May disrupt the hypocretin neurons or their connections to REM- and wake-regulatory regions

19 Narcolepsy from a hypothalamic stroke
Figure. (A) Diagram of a sagittal section of the brain adapted from von Economo1; the hatching highlights those regions in which inflammatory lesions produced hypersomnia. (B, C) T1-weighted sagittal and horizontal MR images demonstrating ex vacuo changes (between arrows) in the posterior hypothalamus and rostral midbrain of the patient with secondary narcolepsy. Th = thalamus; o = optic nerve; Hy = hypothalamus; N. oculomot = occulomotor nerve. Scammell T et al. Neurology 2001;56:

20 Clinical Features

21 Tetrad of Narcolepsy Symptoms Prevalence Excessive sleepiness
Cataplexy Hypnagogic hallucinations Sleep paralysis 100% 70% 66% 60% Additionally >50 % of cataplectic patients suffer from disturbed sleep Only one-third of patients will have all of these classic findings.

22 Manifestations of excessive daytime sleepiness(EDS)
Tendency to fall asleep easily Sleep attacks Frequent daytime napping Amnesic episodes of automatic behavior Memory disturbance and impaired concentration Visual disturbances Most narcolepsy patients have an ESS >16

23 EDS in Narcolepsy Cardinal and often most disabling symptom
Can manifest differently in each individual Fatigue, tiredness, mood changes, difficulty concentrating, mental cloudiness, irritability Most likely to occur in monotonous situations. Naps may be refreshing but only for short period of time

24 Cataplexy criteria Recurrent, brief episodes of muscle weakness triggered by emotions such as laughing, anger, elation, surprise Knee buckling, weakness in legs, jaw, head, neck; sometimes complete fall w/o injury Most episodes are bilateral Consciousness is maintained, at least at the beginning Rarely happens alone – more common in social situations Most episodes last less than 2 minutes

25 Spectrum of cataplexy Cataplexy is pathognomonic for narcolepsy.
Can be described differently between patient’s. Presentation can vary widely: Drooping eyelids, jaw weakness, slurred speech, facial sagging, facial twitching, neck weakness, head drop, shoulder weakness, arm weakness, hand weakness, dropping things, buckling of the knees.

26 Cataplexy Onset Onset of EDS and cataplexy often occur together
Onset of cataplexy may be delayed for years to decades Onset can range from 0 months to >40 years after the onset of EDS

27 Hypnagogic hallucinations
Vivid, often frightening visual, tactile, or auditory hallucinations that occur as the patient is falling asleep Mixture of wakefulness and REM sleep Hypnopompic hallucinations are similar but occur upon awakening and are less common

28 Sleep paralysis Complete inability to move for one or two minutes immediately after awakening, may occur just before falling asleep Frightening episodes that can be associated with hypnopompic hallucinations or a sensation of suffocation Can occur in normal individuals, especially after periods of sleep deprivation The feeling of suffocation may be related to a reduction in tidal volume that occur during sleep paralysis.

29 Other clinical features
Fragmented sleep Higher incidence of other sleep disorders OSA PLMS RLS REM sleep behavior disorder Sleepwalking Depression Obesity Patients with narcolepsy generally fall asleep rapidly but can spontaneously awaken several times during the night and have difficulty returning to sleep. This sleep maintenance insomnia seems paradoxical in a disorder characterized by daytime sleepiness, and it may reflect a low threshold to transition from sleep to wakefulness. People with narcolepsy have a higher than expected incidence of obstructive sleep apnea, periodic limb movements of sleep, restless legs syndrome, REM sleep behavior disorder, sleepwalking, and other sleep disorders [98-102]. This was illustrated by a single-center clinical and polysomnographic study that included 100 consecutive patients with narcolepsy, in which the most common comorbid sleep disorders were insomnia (28 percent), REM sleep behavior disorder (24 percent), restless legs syndrome (24 percent), obstructive sleep apnea (21 percent), and non-REM sleep parasomnias (10 percent) [103]. Identification and treatment of concurrent sleep disorders is important because such disorders may contribute to a patient's daytime sleepiness. Mild obesity is common, and weight gain at the onset of narcolepsy can be dramatic in children and sometimes accompanied by precocious puberty

30 Diagnosis of narcolepsy
Detailed history, physical exam, screening tools, sleep diary Polysomnography MSLT following day HLA typing not diagnostic Hypocretin/orexin measurements

31 E S

32 Swiss Narcolepsy Scale(SNS)
Patients rate the frequency of individual symptoms based on a 5-point scale7 From 1, indicating "never" to 5, indicating "almost always" Each answer is weighted by a positive or negative factor, according to the following equation7,9 (6 x Q1) + (9 x Q2) – (5 x Q3) – (11 x Q4) – (13 x Q5) + 20 A total SNS score of less than 0 is suggestive of narcolepsy with cataplexy7,9 In a study that included patients with narcolepsy with cataplexy, an SNS score of less than 0 was found to have a sensitivity of 96% and a specificity of 98%9 In an additional study that included patients with narcolepsy with cerebrospinal fluid hypocretin-1 deficiency, an SNS score of less than 0 was reported to have a sensitivity of 93% and a specificity of 92%8

33 YES, there’s an App for that

34 Nocturnal polysomnography findings
Short sleep latency Sleep onset REM periods occurs in about 50% of narcolepsy-cataplexy Increased arousal and stage 1, low sleep efficiency Periodic leg movements in 40% of cases Sleep apneas, not unusual if patient is overweight

35 The 30-second epoch of PSG shows sleep onset at 12:18 AM with electroencephalogram (EEG) showing stage 1 sleep. The EEG shows loss of alpha waves in the first 5 seconds (O2-A1, O1-A2). The electro-oculogram (ROC, LOC) shows slow eye movements of drowsiness

36 The 30-second epoch of PSG shows onset of REM sleep with EEG (C4-A1, C3-A2) showing saw tooth waves. The electro-oculogram (ROC, LOC) shows rapid eye movements (note the contour is sharp). Note that at the time 12:20 AM (bottom), 2 minutes after sleep onset as seen in Fig 1, REM sleep was observed.

37 Multiple Sleep Latency Test
Standardized protocol Four to five 20-minute naps Always performed after nocturnal PSG with at least 6 hours of documented sleep Advise and document sufficient sleep 1-2 weeks prior to MSLT After appropriate withdrawal of any psychotropic drugs Measures sleep latency and REM sleep onset

38 MSLT Limitations >6 hours of sleep can be inadequate during the preceding PSG night → children, adolescents, prolonged sleep deprivation False negative rate of 20-30% Less diagnostic in older patients due increased sleep latency and reduction in REM sleep SOREM occur commonly in shift workers, insufficient sleep, untreated OSA, circadian phase delay 5-10 % of general population have 2 or more SOREMPs REM suppressant medications can prevent SOREMPs, and withdrawal can produce REM rebound Also affected by hypnotic agents, ETOH, and caffeine

39 HLA testing Not recommended in routine diagnostic testing
Primarily a research tool Most patients with narcolepsy are DQB1*0602 positive, but is not specific: 12-40% of healthy Americans are + for the haplotype 99% of DQB1*0602 positive individuals do not have narcolepsy Can be useful in patient’s with questionable narcolepsy when additional evidence is needed

40 CSF hypocretin level measurement
Primarily a research tool Not recommended in routine diagnostic testing Can be helpful in certain situations: MSLT difficult to interpret → insomnia, sleep apnea, circadian sleep disorders Inability to discontinue antidepressants prior to testing Atypical cataplexy (90% of patients with true cataplexy have low hypocretin levels) Center for Narcolepsy at Stanford University can assay CSF hypocretin-1 for interested clinicians

41 International Classification of Sleep Disorders, 3rd edition, AASM
Narcolepsy with cataplexy requires both of the following: Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months One or both of the following: Cataplexy and a mean sleep latency of < 8 minutes and two or more SOREMPs on standard MSLT. A SOREM (w/in 15 minutes of sleep onset) on the preceding night PSG may replace one of the SOREMPs on the MSLT Low CSF hypocretin-1 concentration

42 International Classification of Sleep Disorders, 3rd edition, AASM
Narcolepsy without cataplexy If there is clinical suspicion for narcolepsy without cataplexy in a patient with chronic daytime sleepiness, the diagnosis should be confirmed with: An overnight polysomnogram followed the next day by an MSLT that demonstrates a mean sleep latency ≤8 minutes and at least two SOREMPs Exclusion of alternative causes of chronic daytime sleepiness by history, physical exam, and polysomnography. Other conditions that cause chronic daytime sleepiness include insufficient sleep, untreated sleep apnea, periodic limb movements of sleep, and idiopathic hypersomnia (chronic sleepiness but without SOREMs or other evidence of abnormal REM sleep). In addition, the effects of sedating medications should be excluded.

43 Differential diagnosis
Sleep disordered breathing Insufficient sleep/sleep deprivation Psychiatric disorders (depression) Idiopathic Hypersomnia and other hypersomnias (i.e. Kleine-Levin syndrome) Chronic fatigue syndrome Hypothyroidism Other sleep disorders (i.e. PLMS) Malingering

44 Treatment of narcolepsy – Non-pharmacologic
Behavioral Scheduled naps – one or two well timed twenty minute naps can improve sleepiness for 1-3 hrs Avoid sleep deprivation, phase shifts, sedating medications, and heavy meals Most likely should avoid sedentary jobs, especially those requiring sustained vigilance Supportive → work environment, driving precautions, support groups, Narcolepsy Association All patients with narcolepsy have some degree of daytime sleepiness. Although a few manage this successfully with only an afternoon nap, most patients require a medication that promotes wakefulness. Such agents improve performance (measured by reaction time and simulated driving tasks), but performance rarely exceeds 70 to 80 percent of normal

45 General considerations
Amphetamines Sympathomimetics – avoid in patients with heart disease, hypertension, arrhythmias. Can cause sudden death. Do EKG first. Potential for anxiety, psychosis, mania May disrupt sleep Rebound hypersomnia common Moderate abuse potential

46 General considerations
Modafinil, armodafinil Interferes with birth control pills Rare Steven-Johnson Syndrome or other drug rash Sometimes less potent than amphetamines Low abuse potential

47 General considerations
Sodium oxybate, GHB Very sedating, discuss home safety Respiratory depressant, can worsen OSA Overdose can cause coma and death Large salt load Some abuse potential

48  Modafinil has become a first line pharmacologic therapy because it provides good control of sleepiness, is generally well tolerated, and illicit use is rare. A non-amphetamine "wakefulness promoting agent," its mechanism of action is not well understood, but it may increase dopaminergic signaling. Armodafinil is the active R enantiomer and has very similar effects. One trial randomly assigned 283 patients with narcolepsy to receive 200 mg/day of modafinil, 400 mg/day of modafinil, or placebo. After nine weeks, patients treated with modafinil at either dose had significant improvements in their Maintenance of Wakefulness Tests and Epworth Sleepiness Scale measurements, without evidence of tolerance to the drug. Similar results were found in a second clinical trial involving 271 patients with narcolepsy. In a small trial that included 13 patients with narcolepsy, patients randomly assigned to modafinil had improved driving performance compared with patients receiving placebo. Modafinil given once in the morning typically promotes wakefulness into the early evening without disrupting nighttime sleep. It is generally started at a dose of 200 mg each morning and then titrated up to 300 or 400 mg as needed. Patients with persistent afternoon sleepiness may benefit from divided dosing with 200 mg in the morning and 200 mg in the mid-afternoon. Doses of armodafinil generally range from 150 to 250 mg each morning.

49 Sodium oxybate — Sodium oxybate, the sodium salt of gamma hydroxybutyrate (GHB), is a metabolite of gamma amino butyric acid (GABA). It may act through GABA-B receptors, but its precise mechanism of action in patients with narcolepsy is unknown [30,31]. Sodium oxybate markedly reduces cataplexy and, therefore, is a good choice for patients with severe cataplexy [32-38]. The reduction in cataplexy develops over several weeks of treatment so doses should be adjusted slowly [34,39]. Sodium oxybate can also decrease daytime sleepiness, perhaps by improving the quality of nighttime sleep [34,35]. In one observational study, sodium oxybate was associated with a 30 percent decrease of subjective sleepiness, assessed by the Epworth Sleepiness Scale [34]. Similarly, another observational study demonstrated improved sleepiness with sodium oxybate, as assessed by the Maintenance of Wakefulness Test [35]. (See "Quantifying sleepiness".) Sodium oxybate is given as a liquid at bedtime, with a second dose 2.5 to 4 hours later; this second dose is necessary as the half-life is only two to three hours (table 1). Patients may initially need to set an alarm clock to remind them to take the second dose, but after a few weeks, many learn to wake around the correct time. An appropriate initial dose is 3 g, twice per night. The dose can be increased up to 4.5 g, twice per night if cataplexy persists. The benefits of sodium oxybate are often apparent in the first few days, but it can take three months or more to achieve the full response [40]; therefore, the dose should be increased slowly (0.75 g increases every two to four weeks), if needed. In a 12-week open-label study of 202 patients with narcolepsy type 1 who were either treatment-naïve or had been previously exposed but not titrated to adequate clinical effect, the majority of patients were much improved (79 percent) or somewhat improved (11 percent) at their final dose level [37]. The two most common final doses were 6 g/night (40 percent) and 7.5 g/night (33 percent).

50 Pitolisant, a novel histamine H3 receptor inverse agonist, may be an effective treatment for cataplexy as well as daytime sleepiness. In a randomized trial of 106 adults with narcolepsy type 1, pitolisant was more effective than placebo at reducing weekly cataplexy rate (75 versus 35 percent relative reduction from baseline rates of 7 to 9 episodes per week) and Epworth Sleepiness Scale scores (5.4 versus 1.9 point reduction from baseline) [47]. Maintenance of wakefulness test (MWT) scores and frequency of hallucinations were also improved compared with placebo. Daily doses ranged from 5 to 40 mg. Treatment-related adverse events were more common in the pitolisant group (28 versus 12 percent), most commonly headache, irritability, anxiety, and nausea. An earlier randomized trial found that pitolisant was more effective than placebo and improved daytime sleepiness to a similar degree as modafinil in 95 adults with narcolepsy [48]. Pitolisant is available in some countries in Europe but is not yet available in the United States

51 Treatment goals To maintain normal alertness during conventional hours or to maximize alertness at important times of the day (eg, during work, school, or driving) Once therapy has been maximized, residual sleepiness is assessed with ESS or MWT Persistently sleepy patients should be counseled to avoid potentially dangerous activities, such as driving Routine follow up to address consistent use of prescribed medications

52 References Ahmed I, Thorpy M. Clin Chest Med. 2010;31(2):371-381.
American Academy of Sleep Medicine. The International Classification of Sleep Disorders. 3rd ed; 2014. American Psychiatric Association. Diagnostic and Statistical Manual on Mental Disorders. 5th ed; 2013. Aran, et al. Sleep Aug;32(8): Okun, et al. Sleep. Vol. 25, No. 1, 2002. Punjabi N et al. Sleep ;23(4); Sturzenegger C, Bassetti CL. J Sleep Res. 2004; 13(4): Scammell, Thomas E. Clinical features and diagnosis of narcolepsy in adults. UpToDate Scammell, Thomas E. Treatment of narcolepsy in adults. UpToDate

53 Thank you

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