1. Hypersomnolence of Central Origin
Zafer Soultan, MD
Director, Pediatric Pulmonary and Sleep Medicine
Upstate, Golisano Children’s Hospital
Syracuse, NY

2. Main sources Classification of Sleep Disorders, AASM, third edition
Sleep Medicine Pearls, Berry, R. third Edition

3. Sleepiness
Inability to stay awake during the major waking episodes of the day.
Large increase in total daily sleep without feeling of restoration
Sleepiness alleviated by naps, but reoccurs shortly
In children:
long night sleep, or reoccurrence of napping
Inattentiveness, emotional liability, hyperactivity and declined school performance
Must occur for at least 3 months
Resulting in irresistible need for sleep or unintended lapses into drowsiness or sleep.

4. Assessing severity; Epworth

5. Assessing severity
Multiple Sleep Latency Test (MSLT): objective measure of sleepiness

7. Before the test
Document adequate sleep for 1-2 weeks: sleep log and/or actigraphy
PSG a night before with 6-7 hours of sleep
Patients free of drugs that influence sleep for 14 days before study

9. What do we measure Mean sleep latency (MSL)
The number of sleep-onset rapid eye movement (REM) periods (SOREMPs)- within 15 minutes of sleep onset.

10. MSLT: MSL > 8 minutes

11. But, what about age variation
Hence, consider MSL < 12 minutes abnormal in children

12. Actigraphy

13. Central Disorders of Hypersomnlence
Narcolepsy type 1
Narcolepsy Type 2
Idiopathic hypersomnia
Kleine-Levin syndrome
Insufficient sleep syndrome, the most common
Narcolepsy or hypersomnia due to medical condition
Hypersomnia due to medications or associated with psychiatric disorder

14. Narcolepsy Type 1 (narcolepsy with cataplexy)
Daily periods of irrepressible need to sleep, or daytime lapses into sleep
One, or both of the following
Cataplexy and a mean sleep latency of ≤ 8 minutes and 2 or more SOREMP
CSF hypocretin -1 of ≤ 110 pg/ml or < 1/3 mean value of normal

15. Sleepiness in narcolepsy
Daily episodes of irresistible need to lapse into sleep
Patient awaken refreshed
Likely to occur in monotonous situations that require no active participation
Physical activity may suppress the urge to sleep
Sleep attacks in unusual situations- eating or walking

16. Cataplexy
Brief (< 2 minutes) of usually bilateral and symmetrical loss of muscle tone with retained consciousness
Precipitated by strong emotions- laughter, anticipation of an award (children)
In children: facial hypotonia (or generalized) with droopy eyelids, mouth opening, and protruded tongue, or gait unsteadiness

17. Cataplexy

18. Associated features Disruption of nocturnal sleep
Hypnagogic hallucinations and/or sleep paralysis occur in 33-80%
Obesity
Depressive symptoms, anxiety (20%)
Sleep: REM sleep behavior disorder, OSA, PLMD, sleep talking
Fatigue

19. Narcolepsy type 1 Onset 10-25 years, and rare before 5-year age
Sleepiness and then cataplexy within 1-5 years. Rarely, cataplexy may precede sleepiness.
Usually stable when fully developed over the first few years, but cataplexy may decrease, or increase.

20. Demographics/Etiology (genetics, HLA typing)
1/4000 in western European. 7/4000 in Japan
Head trauma, viral illness, seasonal patterns (in the spring)
Autoimmune?
Increased in antibodies against beta-hemolytic streptococcus
In winter after vaccination against H1N1 associated influenza (pandemrix), a dramatic spike in new cases of narcolepsy
Familial? all patients are positive for HLA DQB1*0602
But, the risk of narcolepsy type 1 in first degree relatives is 1-2%, and only 30% chance in identical twin

21. Children Rare prior to age of 4 years
Sleepiness may be difficult to asses, or the child may exhibit hyperactive behavior and deterioration in school performance
Catplexy; weakness on the face, eyelids and mouth, tongue protrusion (cataplectic facies).
MSLT?
CSF Hypocretin-1 is highly sensitive and specific test

22. Neurobiologic Mechanisms of Narcolepsy.
Figure 2 Neurobiologic Mechanisms of Narcolepsy. The neurons that normally produce orexin help sustain wakefulness by stimulating a variety of wakefulness-promoting neurons in the cortex, brain stem, and basal forebrain (Panel A). With loss of the orexin-producing neurons in people with narcolepsy, neurons in these target regions may fire less consistently, leading to sleepiness and lapses into sleep. These neurons also excite brain-stem regions that suppress rapid-eye-movement (REM) sleep (Panel B). Strong positive emotions are thought to activate neurons in the medial prefrontal cortex that excite the orexin-producing neurons and the amygdala. With loss of the orexin neurons in narcolepsy, imbalance in this pathway inhibits brain regions that suppress REM sleep, thus permitting the activation of descending pathways that strongly inhibit motor neurons; the result is partial or complete cataplexy. Pathways shown in green are excitatory; those shown in red are inhibitory. Open circles indicate neuron-cell bodies, and dotted lines indicate reduced activity.
Scammell TE. N Engl J Med 2015;373:

23. Hypocretin deficiency in human narcolepsy
Nishino S. The Lancet 355(9197):39–40, 2000

24. PSG SORMP, very specific but not sensitive REM sleep without atonia
Disruption of sleep with frequent awakenings
Increased N1

25. Polysomnography in narcolepsy
Meir H. Kryger, MD, Atlas of Clinical Sleep Medicine

26. MSLT in narcolepsy
Meir H. Kryger, MD, Atlas of Clinical Sleep Medicine

27. Treatments

29. Narcolepsy type II
Daily periods of irrepressible need to sleep, or daytime lapses into sleep
Cataplexy is absent
A mean sleep latency of ≤ 8 minutes, and 2 or more SOREMP (one SOREMP in the PSG a night before replaces one of the SOREMP on MSLT)
CSF hypocretin -1: > 110 pg/ml (immunoreactive assay) or > 1/3 of mean values of normal individuals obtained with the same assay

30. Demographic/predisposing factors/complications and prognosis
15-25% of the clinic narcoleptic patients
Low Hcrt-1 in 24%, 8% will have intermediate level.
10% of patients will progress to type 1
45% of total narcolepsy type II will have HLA DQB1*0602 positive
The number of hypocretin producing cells are decreased
Triggers unknown: ?head trauma and viral illness
Starts in adolescence

31. Children Sleepiness may present with reappearance of regular napping
MSLT: no normative data in children < 6-year.
Adolescents: the most common etiologies of short sleep onset in MSLT, often with multiple SOREMPs, are chronic sleep deprivation and delayed sleep phase disorder
Behavioral problems may occur at the onset of the disorder. Symptoms may be hidden by the patients.
Inattentiveness, insomnia, lack of energy, bizarre hallucinations, or combination thereof can lead to psychiatric misdiagnosis

32. Differential diagnosis
Idiopathic hypersomnia:
Similar sleep onset on MSLT, but < 2 SOREMP’s on MSLT/PSG
Long unrefreshing naps
High sleep efficiency and sleep drunkenness
OSA
Chronic sleep deprivation
Circadian Rhythm disorders; delayed phase and shift work
Malingering, and substance abuse, and medications
Chronic fatigue

33. Narcolepsy 1 and 2 patients often are
Failing in school, and often dismissed from their jobs.
Driving may be avoided for fear of a motor vehicle accident.
The inability to sleep at night may further contribute to a loss of control these patients have over their schedule.
Depression and weight gain are common

34. Medical Disorders causing Narcolepsy
Narcolepsy Type 1 (N+C)
Narcolepsy Type 2 (N-C)
Tumors, sarcoidosis, arteriovenous malformations affecting the hypothalamus Multiple sclerosis plaques impairing the hypothalamus Paraneoplastic syndrome anti-Ma2 antibodies Neiman-Pick type C disease Possibly Coffin-Lowry syndrome
Head trauma Myotonic dystrophy Prader-Willi syndrome Parkinson disease Multiple system atrophy
N + C, narcolepsy with cataplexy; N−C, narcolepsy without cataplexy.

36. Idiopathic Hypersomnia (IH)
Daily periods of irrepressible need to sleep, or daytime lapses into sleep
No cataplexy
MSLT: < 2 SOREMP’s, or no SOREMP’s if the REM onset on PSG was ≤ 15 minutes
Mean sleep onset latency on MSLT ≤ 8 min, OR total 24-hour sleep ≥ 11 hours on PSG or actigraphy with sleep log
Insufficient sleep syndrome is ruled out

37. Additional features Sleep drunkenness
Long unrefreshing naps (>1 hour)
High sleep efficiency (>90%) on PSG
Autonomic system disturbance: headache, orthostatic disturbance, perception of temperature dysregulation, Raynaud phenomena, sleep paralysis and hypnogogic hallucination

38. IH Unknown pathophysiology Onset adolescents 16-21 years of age
Remission in 14%

39. Differential diagnosis
Narcolepsy II
OSA
Chronic fatigue
Hypersomnia with medical or psychiatric disorders, due to medications or substance
Long sleepers

40. Kleine-Levin syndrome
At least 2 recurrent episodes of excessive sleepiness and sleep duration, each persisting for 2 days-5 weeks
Episodes recur more than once in 1 year, and at least once every 18 months
Normal alertness, mood, cognitive function and behavior between episodes

41. Kleine-Levin syndrome
At least one of the following during the episode:
Cognitive dysfunction
Altered perception
Eating disorder
Disinhibited behavior (such as hypersexuality)
Sub-type: Menstrual-related Kleine-Levin Syndrome

42. Kleine-Levin Syndrome
Incidence 1-2 per million
Male/Female: 2:1
Starts in second decade of life and remits in 14 years

43. Insufficient sleep syndrome
Daily periods of irrepressible need to sleep or daytime lapses into sleep or, in the case of prepubertal children, there is a complaint of behavioral abnormalities attributable to sleepiness
Sleep time is shorter than expected for age
The patient curtails sleep time
Extension of total sleep time results in resolution of the symptoms of sleepiness

44. Associated features
Irritability, concentration and attention deficits, reduced vigilance, distractibility, reduced motivation, anergia, dysphoria, fatigue, restlessness, uncoordination and malaise
Common in adolescence
Diagnosed by 2-3 weeks of sleep diary and actigraphy
PSG; increased sleep efficiency.
MSLT excessive sleepiness, no SOREMP’s, and excessive N1

45. Long Sleeper > 10 hours in adults
2 hours more than age-specific norms.
Sleepiness when they are forced to curtail their sleep time
It begins in childhood

47. Case 1 17-year old male, EDS started at 9th grade No cataplexy
No snoring

48. Actigraphy Monday 1 am-6:45 am Tuesday 1:10 am- 7 am Wednesday
Thursday
1:10 am- 6:45 am
Friday
1:45 am-10 am
Saturday
2 am-10:30 am
Sunday
1:15 am-6:50am

51. What is the diagnosis
Insufficient sleep syndrome

52. MSLT in adolescents
MSLT in 10th graders (26 subjects), two SOREMPs were seen in 16% of the participants and one SOREMP was noted in 48%Carskadon A.R 1998  
The majority of the SOREMPs were observed in the morning naps. Therefore, one must be cautious about making the diagnosis of narcolepsy in adolescents based on SOREMPs that occur only in the first two naps 

55. Meir H. Kryger, MD, Atlas of Clinical Sleep Medicine

56. 20-year old female Severe daytime sleepiness for over 12 months
Bilateral leg weakness lasting for 1 to 2 minutes when she heard or told a joke or was embarrassed. As they came on slowly, she was able to sit down or support herself and had never fallen.
No medications
Adequate sleep for 7 hours, and sleeping longer did not improve the daytime sleepiness.
Often fell asleep in class.
She did report waking up and being weak for a few seconds. No history of sleep associated hallucinations or dreams, or snoring was present.

58. What is the diagnosis?
Narcolepsy type?
Type 1

59. REM sleep
REM sleep normally occurs only during the usual sleep period and includes vivid, storylike dreams, rapid eye movements, and paralysis of nearly all skeletal muscles, except the muscle of ----
respiration

61. What is this symptom?
Patient states he dreamed he was eating shredded wheat and woke up to find the mattress half gone.
REM sleep behavior disorder

62. Diagnosis
Characteristics
Insufficient sleep
Sleepiness decreases with more sleep on weekends
OSA
Snoring, apnea, large tonsils etc.
Narcolepsy
Cataplexy, Hypnagogic and hypnopompic hallucinations, sleep paralysis, fragmented sleep
Delayed sleep phase disorder
Sleepiness in the am, alertness at night
Shift-work sleep disorder
Sleepiness when working at night, insufficient sleep during the day
Use of sedating medications
Idiopathic hypersomnia
Lengthy nighttime sleep and long naps, difficulty waking from sleep
Depression
Increased time in bed, but negative MSLT
Other medical disorders
Parkinson’s disease, Prader-Willi syndrome, Myotonic dystrophy, among others

63. The Meaning Of Dreams
After she woke up, a woman told her husband, "I just dreamed that you gave me a diamond necklace for our anniversary. What do you think it means?" "You'll know tonight." he said. That evening, the man came home with a small package and gave it to his wife. Delighted, she opened it to find a book entitled "The Meaning of Dreams.”