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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