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IL SONNO VISTO
DAL
NEUROLOGO
Luigi Ferini Strambi
Università Vita-Salute
San Raffaele, Milano
PARAMETRI FISIOLOGICI PER LA DEFINIZIONE
DEL SONNO
C
MS D
R
IPNOGRAMMA
Pre - sleep - W
SWS
REM - sleep
Post - sleep - W
ACTIVATION
ACTIVATION
High
High DEACTIVATION
DEACTIVATION
Low
Low DEACTIVATION
DEACTIVATION
BRAUN et al; Brain (1997)
Dijk and Edgar, 1999, Lung Biology in Health and Disease, vol.133
Arousal
Sleep
No sleep
20
20
15
15
Cortisol
10
10
(µg/dl)
5
5
0
10
05
14
18
22
02
06
10
0
10
05
04
04
Thyrotropin
03
03
(µU/ml)
02
02
01
10
01
10
Prolactin
(ng/ml)
(µg/L)
18
22
02
06
10
25
25
20
20
15
15
10
10
5
5
0
10
Growth
Hormone
14
14
18
22
02
06
10
0
10
20
20
15
15
10
10
5
5
0
10
14
18
22
02
06
10
0
10
14
18
22
02
06
10
14
18
22
02
06
10
14
18
22
02
06
10
14
18
22
02
06
10
Clock Time
acute
sleep
deprivation
Cortisol rhythm
Sleep loss impairs the human antibody response to
hepatisis A vaccination
total loss of sleep in the night following vaccination
impairs immune response 28 days later
Lange et al (2003) Psychosomatic Medicine 65: 831-835
Response to influenza vaccination is impaired
in individuals with chronic partial sleep restriction
Sleep restriction to 4 hours/night, for 4 days before and 2 days after vaccination,
impairs immune response to vaccination
Spiegel et al (2002) JAMA 288: 1471-1472
Structural MRI of the brains of humans with
extensive navigation experience, licenced
London taxi drivers, were analysed and
compared to those of control subjects who
did not drive taxi.
The posterior hippocampi of taxi drivers
were significantly larger relative to those
of controls.
A more anterior hippocampal region was
larger in controls than in taxi drivers…..
Mechanism of brain damage:
Neurogenic or vasogenic ?
Potential contributors of cognitive impairment:
Hypoxemia or sleep fragmentation ?
Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive
Impairment and Dementia in Older Women
Yaffe K et al, JAMA 306: 613-19, 2011
Compared with the 193 women without sleep-disordered breathing,
the 105 women (35.2%) with sleep-disordered breathing were more
likely to develop mild cognitive impairment or dementia (adjusted
odds ratio,AOR = 1.85).
Elevated oxygen desaturation index (≥15 events/hour) and high
percentage of sleep time (>7%) in apnea or hypopnea (both
measures of disordered breathing) were associated with risk of
developing mild cognitive impairment or dementia (AOR= 1.71 and
2.04 respectively).
Measures of sleep fragmentation (arousal index and wake after sleep
onset) were not associated with risk of cognitive impairment.
The hippocampus is one of the main and most consistently
reported brain regions among the neural correlates of mild
cognitive impairment…………..
No medications are known to prevent the progression of mild
cognitive impairment to Alzheimer’s disease, so treating at-risk
patients with CPAP for sleep-disordered breathing is a
prevention strategy that may be worth testing.
Neurocognitive Function
58 memory impaired
OSA patients
Neuropsychological Testing
3 months CPAP
Neuropsychological Testing
+ Compliance
•
•
Poor Users
<2 h/night
Moderate Users
2-6 h/night
Optimal Users
>6 h/night
Odds of optimal users exhibiting
normalization of memory function were 7.9
times (p 0.01) the odds of poor users
Normalization of memory abilities in:
21 % of poor users
44 % of moderate users
68 % of optimal users
Zimmerman et al. CHEST, 2006
International Classification of
Sleep Disorders, 2005
•
•
•
•
•
•
INSOMNIA
SLEEP-RELATED BREATHING DISORDERS
HYPERSOMNIA OF CENTRAL ORIGIN
CIRCADIAN RHYTHM SLEEP DISORDERS
PARASOMNIAS
SLEEP RELATED MOVEMENT DISORDERS
Luyster F et al
Chen R et al
PERIODIC LEGS MOVEMENTS
(PLMs)
Restless Legs
Syndrome:
Essential criteria
1) An urge to move the legs
2) that is present at rest
3) relieved by movement, and
4) demonstrates a circadian
pattern (peak symptoms
occurring at night or in the
evening)
Diagnostic criteria for RLSNon essential but common features
• Family history
• Response to dopaminergic therapy
• Experience of PLM during sleep or during
wakefulness
• Sleep disturbance
• An increase in severity with advancing age
Allen et al Sleep Med 2003
PD patient, 69 y, male
AHI= 21
PLMI= 28
Eur Res J in press
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.
RLS patients show significant sleep
microstructure abnormalities
(increased cortical arousals).
Acute pramipexole administration
seems to exert no action on these
abnormalities and the moderate
effects seen on sleep architecture
might be interpreted as the
beneficial consequence of the
removal of pre-sleep RLS
symptoms and PLMS.
PLMS
CORTICAL
AROUSALS
AUTONOMIC
AROUSAL
INSOMNIA
CV RISK
SLEEPINESS CHARACTERISTICS
Narcolepsy
Repeated refreshing naps of short
duration (<1hr)
Recurrent hypersomnia
Recurrent episodes of 18-20 hrs lasting
3-20 days, 1-3 years
Idiopatic hypersomnia
Prolonged (1-2 hrs) sleep episodes of
NREM sleep and major sleep episode >8
hrs
Post-traumatic
hypersomnia
As above. However, the sleepiness is most
evident in the immediate post-traumatic
period and resolves over weeks to
months
OSA
Sleepiness in a relaxing situation;
unrefreshing naps (variable
duration)
Insufficient sleep syndrome
Sleepiness is not present during
weekends or vacation time
Narcolepsy
 A disease characterized by loss of clear
boundaries between sleep & wake
 Narcolepsy is characterized by severe
sleepiness, frequent unwanted transitions
into sleep during wakefulness as well as
frequent periods of awakenings during sleep
 Patients with narcolepsy can quickly enter
REM sleep at anytime of the day
 Patients also experience REM sleep-like
episodes intruding into wakefulness, such as
loss of muscle tone while awake, a condition
known as cataplexy
Dauvilliers et al. Neurology 2001;57:2029-2033; Okun et al. Sleep 2002;25:27-35..
Narcolepsy/Cataplexy Prevalence
Estimates Differ Between Ethnic Groups
0.59%
% of population
0,60
Low estimate
High estimate
0,50
0,40
0,30
0.16%
0,20
0,10
0.026% 0.035%
0.002%
0
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
Narcolepsy:
Constellation of Symptoms
 Excessive daytime sleepiness
 Cataplexy and other REM phenomena

Hypnagogic/hypnopompic hallucinations

Sleep paralysis
 Fragmented sleep
 Automatic behaviors
Guilleminault. Narcolepsy syndrome. In: Principles and Practice of Sleep Medicine. 1994.
Hypocretin Deficiency
in Human Narcolepsy
CSF hypocretin (pg/mL)
700
600
500
400
47
10
18
3
0
88
3
300
200
100
0
Control
(n=47)
Mignot et al. Arch Neurol. 2002;59:1553.
Narcolepsy
with
cataplexy
(n=101)
Narcolepsy
without
cataplexy
(n=20)
Pre-motor features of Parkinson's disease: the
Honolulu-Asia Aging Study experience
Ross GW et al., Mov Disord 2012
The Honolulu-Asia Aging Study is a population based prospective study of
neurodegenerative and cerebrovascular diseases in 8006 Japanese-American
men, born 1900-1919. Beginning in 1965, environmental, life-style, and
physical characteristics, including many features associated with pre-motor
Parkinson's disease (PD), were ascertained at examinations over 40 years.

Impaired olfaction, constipation, slow reaction time, excessive
daytime sleepiness, and impaired executive function were all
associated with future development of PD and/or with
increased likelihood of either incidental Lewy bodies.
Compared with persons without any, those with combinations of
2 or more of these pre-motor features had up to a 10-fold
increase in risk for development of PD.
CPAP improves sleep and daytime
sleepiness in patients with PD and sleep
apnea
Neikrug AB et al., Sleep 37: 177-85, 2014
- Randomized placebo-controlled, cross over study
-38 PD patients, treated for 6 weeks
- CPAP treated patients showed significantly decrease
in AHI and Arousal index, and increase in N3 stage %
- CPAP also reduced daytime sleepiness, measured by
MSLT
CLASSIFICAZIONE INTERNAZIONALE: PARASONNIE
DISTURBI DELL’AROUSAL
• SONNAMBULISMO
• PAVOR NOCTURNUS (INCUBI)
DISTURBI DEL PASSAGGIO SONNO-VEGLIA
• MOVIMENTI RITMICI DEL SONNO (STEREOTYPED PARASOMNIAS)
• MIOCLONIE IPNICHE
• SONNILOQUIO
PARASONNIE ASSOCIATE AL SONNO REM
• SOGNI TERRIFICI
• REM SLEEP BEHAVIOR DISORDER
ALTRE PARASONNIE
• BRUXISMO
• ENURESI NOTTURNA
• DISFAGIA NOTTURNA SALIVARE
• DISTONIA PAROSSISTICA NOTTURNA
• MORTE IMPROVVISA IN SONNO (DA CAUSA SCONOSCIUTA)
•SINDROME DELLA MORTE IMPROVVISA DEL LATTANTE
• SINDROME DA IPOVENTILAZIONE CENTRALE CONGENITA
• MIOCLONO BENIGNO NEONATALE IN SONNO
Sleep Terrors
Differential diagnosis:
Part of the night
Major motor
activity
Anxiety
Vocalization
Autonomic
discharge
Intellectual function
SLEEP
TERRORS
NIGHTMARES
First third
++
Last third
+/-
+++
++
+++
++
+
+
-(Confusion)
+(Good)
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
REM SLEEP BEHAVIOR DISORDER
Some clinical aspects of RBD
 Estimated
 Male
 Age
prevalence  0.04-0.5%
prevalence (M/F: 9/1)
of onset: 52.6  16 yrs
 Altered
dream content or enacting
behaviors: 92%
Clinical RBD course
acute
alcohol (withdrawal)
tryciclic antidepressants (intoxication or
withdrawal)
anti-MAO, caffeine (intoxication)
RBD
25% Idiopathic form
chronic
Consequent symptom
Initial manifestation
75% symptomatic form
(neurological diseases)
NEUROLOGY 2005; 64:780-786.
•
•
•
•
Impairment of cortical activity
Neuropsychological deficits
Autonomic dysfunctions
Olfactory deficits
Does the idiopathic form of RBD really exist?
INCREASED AGGRESSIVE DREAM CONTENT
WITHOUT INCREASED DAYTIME AGGRESSIVENESS
IN REM SLEEP BEHAVIOR DISORDER
ML Fantini, A Corona, S Clerici and L Ferini-Strambi
Neurology, 2005
RESULTS – Daytime aggressiveness
• No between-group difference in overall daytime aggressiveness
• Patients with RBD showed lower score on “Physical Aggression”
than controls
RBD
patients
Controls
p
69.9 ± 16.1
73.8 ± 20.3
0.37
Physical Aggression
16.5 ± 6.4
20.4 ± 8.3
0.034
Verbal Aggression
15.0 ± 4.2
14.4 ± 4.0
0.59
Anger
17.9 ± 6.5
17.3 ± 6.0
0.67
Hostility
20.4 ± 5.4
21.6 ± 6.2
0.38
AQ total score
• Two patients with RBD and 4 controls had an AQ score >96,
which is considered suggestive of daytime aggressiveness.
RESULTS – Dream content
• Compared to control subjects, RBD showed:
 Dreams with at least one aggression
(66% vs. 15%;
p<0.00001)
 ratio Aggression/Friendliness interactions (89% vs.
44%; p<0.0001)
 frequency of Animal characters
(19% vs. 4%: p=0.0001)
No Dreams with at least one element of sexuality (0%
vs. 9%; p<0.0001)
RBD:
DIFFERENTIAL DIAGNOSES
 Sleepwalking
and sleep terrors
(possibility of overlap)
 Nocturnal seizures
 Obstructive sleep apnea (OSA) with
agitated REM-related arousals
 Psychogenic dissociative disorders