1. Disturbi neurologici nel sonno che lo pneumologo deve conoscere
Luigi Ferini-Strambi
Centro di Medicina del Sonno
Università Vita-Salute San Raffaele, Milano

2. INSONNIE
Le tre donne, Pablo Picasso
Pablo Picasso

11. IPERSONNIE
Gustav Klimt
Danae, Gustav Klimt

12. Narcolepsy: Epidemiology
Men affected somewhat more often than women
Age at onset
From childhood to the early fifties
Mean age at onset: 24 years
Two peaks:
A major one at approximately 15 years of age
A secondary one at approximately 36 years of age
Clinical presentation and natural history of narcolepsy-cataplexy similar across ethnic groups
Dauvilliers et al. Neurology 2001;57: ; Okun et al. Sleep 2002;25:

13. Narcolepsy/Cataplexy Prevalence Estimates Differ Between Ethnic Groups
0.59%
Low estimate
High estimate
% of population
0.16%
This figure illustrates the considerable variations in the prevalence of narcolepsy/cataplexy that have been reported in various populations/nations.
0.026%
0.035%
0.002%
Western Europe/
North America
Japan
Israel
Hublin et al. Ann Neurol 1994;35:709. Silber et al. Sleep 2002;25:197. Honda. Sleep Res 1979;8:191. Tashiro et al. J Sleep Res 1992;1:228. Wilner et al. Hum Immunol 1988;21:15. Ohayon et al. Neurology 2002; 58:1926. Zeman et al. BMJ 2004; 329:724
Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(suppl 1):S16-S22.

14. How Long is it Before Narcolepsy is Diagnosed?
Total Onset vs Total Diagnosis
400
Onset (N=992)
Diagnosis (N=1029)
300
Number of respondents
200
The symptoms of narcolepsy start before the age of 25 years in 70% to 80% of patients, with onset peaking in the late teens.
The average delay in diagnosis is approximately 10 years.
100
0-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
Age (years)
Courtesy of M. Thorpy, MD.

15. Narcolepsy: Constellation of Symptoms
Excessive daytime sleepiness
Cataplexy and other REM phenomena
Hypnagogic/hypnopompic hallucinations
Sleep paralysis
Fragmented sleep
Automatic behaviors
Narcolepsy is a chronic neurologic disorder that is characterized by a failure to maintain normal boundaries between REM sleep and the waking state coupled with CNS dysfunction in capacity to maintain normal wakefulness and sleep. This manifests through a constellation of clinical symptoms of varying frequency and severity.
Various reports describe widely varying prevalence rates for the symptoms of narcolepsy.
The most prevalent symptom is excessive daytime sleepiness, which occurs in 100% of patients diagnosed with narcolepsy.
Often considered pathognomonic for narcolepsy, cataplexy is the second most common symptom, occurring in 60% to 100% of patients.
Hypnagogic/hypnopompic hallucinations occur in 15% to 80% of patients, often in conjunction with sleep paralysis.
Fragmented nighttime sleep occurs in 60% to 90% of narcoleptic patients.
Automatic behaviors occur in 40% to 50% of patients.
Medical terminology used to define the constellation of symptoms include:
Narcolepsy tetrad = excessive daytime sleepiness, cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis
Narcolepsy pentad = the tetrad + fragmented sleep
Guilleminault. Narcolepsy syndrome. In: Principles and Practice of Sleep Medicine
Guilleminault C. Narcolepsy syndrome. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 2nd ed. Philadelphia, Pa: W.B. Saunders; 1994:
Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18:
Thorpy M. Current concepts in the etiology, diagnosis and treatment of narcolepsy. Sleep Med. 2001;2:5-17.
Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin. 1996;14:

16. Cataplexy: Clinical Presentations
Ptosis
Sagging jaw
Hypophonic/slurred speech
Nodding head
Arm or leg weakness (knee buckling)
Generalized weakness/paralysis
Ventilatory muscles spared
Muscle twitching
Anic-Labat et al. Sleep 1999;22:77.
Anic-Labat S, Guilleminault C, Kraemer HC, et al. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep. 1999;22:77-87.

17. Cataplexy: Emotional Triggers
% of patients with trigger
100
87% 80
73%
68%
65.6%
58.1% 60
54%
50% 40
22% 20
One of the most specific ways to distinguish cataplexy from other known nonspecific episodes of muscle weakness is to ask about triggering factors.
These data are from a study that included 63 patients with “clear-cut” narcolepsy and show the emotional triggers that most frequently provoked an episode of cataplexy. These triggers help differentiate cataplexy from other conditions of motor weakness.
The most common trigger is laughter.
The most specific trigger is joking.
Anger and stress are frequent triggers of cataplexy, but independently are not sufficient for diagnosis of cataplexy.
Sex occasionally triggers cataplexy, but is neither specific nor sensitive.
It is important to note that even the anticipation of a response can often provoke a cataplectic episode—for example, remembering an emotional moment or a happy thought.
Sex
Joking
Anger
Stress
Laughter
Surprise
Excitation
Startlement
Adapted from Anic-Labat et al. Sleep 1999;22:77.
Anic-Labat S, Guilleminault C, Kraemer HC, et al. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep. 1999;22:77-87.

18. Hallucinations
Vivid, dreamlike hallucinations that occur during transitions between wakefulness and sleep
Hypnagogic at sleep onset (most common)
Hypnopompic at awakening
Multisensory
May accompany sleep paralysis
Some awareness of surroundings is preserved
Frightening/disconcerting
Hallucinations are usually bizarre, frightening, and appear very real to the patient; 15% to 80% of patients with narcolepsy experience hallucinations.
The duration of a hallucination is usually <10 minutes and can occur during nocturnal sleep onset, daytime naps/attacks, and at awakening.
Visual imagery is predominant and appears more vivid during hypnagogic hallucinations and when accompanied by sleep paralysis.
Auditory hallucinations are also common and can range from a collection of sounds to an elaborate melody to threatening sentences or harsh invective.
Other common and interesting types of hallucination that occur during sleep onset include out-of-body experiences and cenesthopathic feeling (rubbing, light touching).
Guilleminault and Anagnos. Narcolepsy. In: Principles and Practice of Sleep Medicine, 3rd ed
Guilleminault C, Anagnos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: W.B. Saunders; 2000:

19. Sleep Paralysis Inability to move for a few seconds or minutes
Occurs at sleep onset or upon awakening
Ends spontaneously or after mild sensory stimulation (“shake out of it”)
Medically stable; ventilation, ocular muscles, and awareness preserved; limited vocalization
May accompany hypnagogic/hypnopompic hallucinations
Frightening/disconcerting
Sleep paralysis occurs at sleep onset or, more commonly, upon awakening.1 Adequate ventilation is maintained despite paralysis due to lack of paralysis effect on the diaphragm.
Sleep paralysis may be accompanied by eye fluttering, moaning, tingling or numbness of limbs, autonomic symptoms such as palpitations or sweating, a sensation of struggling to move or breathing difficulty, pressure on the chest, or shortness of breath.2 Ventilation, however, is not negatively impacted during the episode.
Attacks occur in up to 80% of patients with narcolepsy.1
Patients are usually frightened during an attack, particularly the first time. Anxiety can be intensified by hypnagogic hallucinations that can accompany the paralysis.2
Sensory stimulation may end the paralysis.1
“Do you ever feel that you are awake, but you just can’t move at all?”
Overeem et al. J Clin Neurophysiol 2001;18:78; Hishikawa and Shimizu. Adv Neurol 1995;67:245.
1. Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18:
2. Hishikawa Y, Shimizu T. Physiology of REM sleep, cataplexy, and sleep paralyses. Adv Neurol. 1995;67:

20. Fragmented Nocturnal Sleep
Severe disruption of nocturnal sleep may occur in up to 90% of patients with narcolepsy
Frequent awakenings
Fragmented circadian rhythms
Early onset REM periods
Sleep intruding into usual waking hours
Fragmented nocturnal sleep is often mistaken for primary insomnia.1
Most awakenings are brief; however, some patients may stay awake for hours.1
Fragmented sleep is less restorative than consolidated nighttime sleep and leads to sleepiness-related daytime impairment.2
Guilleminault. Narcolepsy syndrome. In: Principles and Practice of Sleep Medicine. 1994; Bassetti and Aldrich. Neurol Clin 1996;14:545.
1. Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin. 1996;14:
2. Stepanski EJ. The effect of sleep fragmentation on daytime function. Sleep. 2002;25:

21. ICSD-2 Diagnostic Criteria for Narcolepsy with Cataplexy
Complaint of EDS for at least 3 months
Typical cataplexy: sudden and transient episodes of loss of muscle tone triggered by emotions including laughter; consciousness preserved
No medical or mental disorder accounts for the symptoms
MSLT findings: mean sleep latency <8 min, 2 SOREMPs; or CSF hypocretin-1 level 110 pg/ml (internationally standardised value)
Minimal criteria: A + B + C
Although excessive daytime sleepiness (EDS) is often the first symptom of narcolepsy, additional symptoms may develop over time. The minimal criteria for diagnosis of narcolepsy are recurrent daytime sleep for at least 3 months plus cataplexy. Alternatively, excessive daytime sleep or sudden muscle weakness combined with associated features such as sleep paralysis, automatic behaviors, disrupted sleep, and hypnagogic hallucinations, as well as a subjective diagnosis using polysomnographic findings and elimination of medical, psychiatric, and other sleep disorders, are all indicative of narcolepsy.
ICSD-2 = International Classification of Sleep Disorders (revised 2004); EDS = excessive daytime sleepiness; MSLT = Multiple Sleep Latency Test; SOREMP = sleep-onset REM period; CSF = Cerebrospinal Fluid.

22. ICSD-2 Diagnostic Criteria Narcolepsy without Cataplexy
Complaint of EDS for at least 3 months
No (typical) cataplexy
No medical or mental disorder accounts for the symptoms
MSLT findings: mean sleep latency <8 min, 2 SOREMPs; or CSF hypocretin-1 level 110 pg/ml (internationally standardised value)
Minimal criteria: A + B + C + D
Although excessive daytime sleepiness (EDS) is often the first symptom of narcolepsy, additional symptoms may develop over time. The minimal criteria for diagnosis of narcolepsy are recurrent daytime sleep for at least 3 months plus cataplexy. Alternatively, excessive daytime sleep or sudden muscle weakness combined with associated features such as sleep paralysis, automatic behaviors, disrupted sleep, and hypnagogic hallucinations, as well as a subjective diagnosis using polysomnographic findings and elimination of medical, psychiatric, and other sleep disorders, are all indicative of narcolepsy.
ICSD-2 = International Classification of Sleep Disorders (revised 2004); EDS = excessive daytime sleepiness; MSLT = Multiple Sleep Latency Test; SOREMP = sleep-onset REM period; CSF = Cerebrospinal Fluid.

25. AUMENTATA ATTIVITA’ MOTORIA NEL SONNO
Ecole d’Avignone
AUMENTATA ATTIVITA’ MOTORIA NEL SONNO

26. Circa la metà dei pazienti OSA presenta irrequietezza motoria durante il sonno
ASDA. The International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Rochester, Minnesota; 1997: 52-8.
Kales A, et al. J Chron Dis 1985; 38:
Maislin G, et al. Sleep 1995; 18:
Coversdale S, et al. Aust N Z J Med 1980; 10: 284-8
Kryger M, Roth T, Dement W. Principle and Practice of Sleep Medicine. WB Saunders Philadelphia 2010

28. Movimenti ripetitivi e stereotipati degli arti durante il sonno
PLM Disorder
Movimenti ripetitivi e stereotipati degli arti durante il sonno
Più frequenti nel sonno 2 NREM
= Frammentazione del sonno
= Sia insonnia che ipersonnia

30. PLM Disorder-Stadiazione
Assente: PLM Index inferiore a 5
Lieve: PLM Index tra 5 e 25
Moderato: PLM Index tra 25 e 50
Grave: PLM Index superiore a 50

31. Increase of heart rate in relation to periodic leg movement (PLM)

32. In RLS, PLMs induce a repetitive rise in blood pressure and heart rate
RLS and periodic limb movements
In RLS, PLMs induce a repetitive rise in blood pressure and heart rate
Pennestri MH, et al. Neurology 2007;68:1213–1218. Siddiqui F, et al. Clin Neurophysiol 2007;118:1923–1930. 32 32

33. Multivariate odds ratios: hypertension adjusted for other variables
Age
OR 4.37 (3.11–6.13)
Male gender
OR 1.26 (0.90–1.77)
Body mass index
OR 1.96 (1.41–2.71)
PLMI mean
5–15
>15–30
>30
OR 1.50 (1.03–2.19)
OR 1.48 (0.94–2.35)
OR 2.26 (1.28–3.99)
PLMI mean >5
OR 1.59 (1.14–2.21)
Subjects and family members (n=861) were recruited from an advertisement describing RLS and provided clinical data. Age gender, body mass index and mean periodic leg movements of sleep (PLMs) were examined as predictors of hypertensive status
Billars L, et al. Sleep 2007;30(Abstract Supplement)A297. Abstract #0869. 33 33

42. NFLE: clinical profile
Age at onset yrs
clusters of nocturnal short (< 60 s) motor seizures (NREM), sometimes prolonged
dystonic-dyskinetic movements with tonic posture, complex motor activities (wandering, pelvic thrusting) or simple repetitive gestures
abrupt, stereotypic and intraindividually repetitive
absence of ictal or interictal EEG abnormalities (rare frontal foci)

43. Rem Sleep Behavior Disorder (RBD)
1986 – 5 patients – Mahowald et al.
RBD is characterized by the intermittent loss of Rem sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation

44. REM SLEEP BEHAVIOR DISORDER

45. Some clinical-PSG aspects of RBD (Ferini-Strambi et al, 2005)
M/F: 9/1
Age of onset: 52.6  16 yrs
Age at presentation: 59.3  15 yrs
Rarely children and adolescent onset
Altered dream process or enacting behaviors92%
PLMS 63% (legs/arms)
 % SWS for age (84%)(% st 3-4 NREM = 25 6)