12Narcolepsy: Epidemiology Men affected somewhat more often than womenAge at onsetFrom childhood to the early fiftiesMean age at onset: 24 yearsTwo peaks:A major one at approximately 15 years of ageA secondary one at approximately 36 years of ageClinical presentation and natural history of narcolepsy-cataplexy similar across ethnic groupsDauvilliers et al. Neurology 2001;57: ; Okun et al. Sleep 2002;25:
13Narcolepsy/Cataplexy Prevalence Estimates Differ Between Ethnic Groups 0.59%Low estimateHigh estimate% of population0.16%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 AmericaJapanIsraelHublin 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; 329:724Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(suppl 1):S16-S22.
14How Long is it Before Narcolepsy is Diagnosed? Total Onset vs Total Diagnosis400Onset (N=992)Diagnosis (N=1029)300Number of respondents200The 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.1000-45-910-1415-1920-2425-2930-3435-3940-4445-4950-5455-5960-6465-6970-74Age (years)Courtesy of M. Thorpy, MD.
15Narcolepsy: Constellation of Symptoms Excessive daytime sleepinessCataplexy and other REM phenomenaHypnagogic/hypnopompic hallucinationsSleep paralysisFragmented sleepAutomatic behaviorsNarcolepsy 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 paralysisNarcolepsy pentad = the tetrad + fragmented sleepGuilleminault. Narcolepsy syndrome. In: Principles and Practice of Sleep MedicineGuilleminault 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:
16Cataplexy: Clinical Presentations PtosisSagging jawHypophonic/slurred speechNodding headArm or leg weakness (knee buckling)Generalized weakness/paralysisVentilatory muscles sparedMuscle twitchingAnic-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.
17Cataplexy: Emotional Triggers % of patients with trigger10087%8073%68%65.6%58.1%6054%50%4022%20One 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.SexJokingAngerStressLaughterSurpriseExcitationStartlementAdapted 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.
18HallucinationsVivid, dreamlike hallucinations that occur during transitions between wakefulness and sleepHypnagogic at sleep onset (most common)Hypnopompic at awakeningMultisensoryMay accompany sleep paralysisSome awareness of surroundings is preservedFrightening/disconcertingHallucinations 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 edGuilleminault 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:
19Sleep Paralysis Inability to move for a few seconds or minutes Occurs at sleep onset or upon awakeningEnds spontaneously or after mild sensory stimulation (“shake out of it”)Medically stable; ventilation, ocular muscles, and awareness preserved; limited vocalizationMay accompany hypnagogic/hypnopompic hallucinationsFrightening/disconcertingSleep 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.1Patients are usually frightened during an attack, particularly the first time. Anxiety can be intensified by hypnagogic hallucinations that can accompany the paralysis.2Sensory 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:
20Fragmented Nocturnal Sleep Severe disruption of nocturnal sleep may occur in up to 90% of patients with narcolepsyFrequent awakeningsFragmented circadian rhythmsEarly onset REM periodsSleep intruding into usual waking hoursFragmented nocturnal sleep is often mistaken for primary insomnia.1Most awakenings are brief; however, some patients may stay awake for hours.1Fragmented sleep is less restorative than consolidated nighttime sleep and leads to sleepiness-related daytime impairment.2Guilleminault. 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:
21ICSD-2 Diagnostic Criteria for Narcolepsy with Cataplexy Complaint of EDS for at least 3 monthsTypical cataplexy: sudden and transient episodes of loss of muscle tone triggered by emotions including laughter; consciousness preservedNo medical or mental disorder accounts for the symptomsMSLT findings: mean sleep latency <8 min, 2 SOREMPs; or CSF hypocretin-1 level 110 pg/ml (internationally standardised value)Minimal criteria: A + B + CAlthough 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.
22ICSD-2 Diagnostic Criteria Narcolepsy without Cataplexy Complaint of EDS for at least 3 monthsNo (typical) cataplexyNo medical or mental disorder accounts for the symptomsMSLT findings: mean sleep latency <8 min, 2 SOREMPs; or CSF hypocretin-1 level 110 pg/ml (internationally standardised value)Minimal criteria: A + B + C + DAlthough 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.
25AUMENTATA ATTIVITA’ MOTORIA NEL SONNO Ecole d’AvignoneAUMENTATA ATTIVITA’ MOTORIA NEL SONNO
26Circa 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: 284-8Kryger M, Roth T, Dement W. Principle and Practice of Sleep Medicine. WB Saunders Philadelphia 2010
28Movimenti ripetitivi e stereotipati degli arti durante il sonno PLM DisorderMovimenti ripetitivi e stereotipati degli arti durante il sonnoPiù frequenti nel sonno 2 NREM= Frammentazione del sonno= Sia insonnia che ipersonnia
30PLM Disorder-Stadiazione Assente: PLM Index inferiore a 5Lieve: PLM Index tra 5 e 25Moderato: PLM Index tra 25 e 50Grave: PLM Index superiore a 50
31Increase of heart rate in relation to periodic leg movement (PLM)
32In RLS, PLMs induce a repetitive rise in blood pressure and heart rate RLS and periodic limb movementsIn RLS, PLMs induce a repetitive rise in blood pressure and heart ratePennestri MH, et al. Neurology 2007;68:1213–1218. Siddiqui F, et al. Clin Neurophysiol 2007;118:1923–1930.3232
33Multivariate odds ratios: hypertension adjusted for other variables AgeOR 4.37 (3.11–6.13)Male genderOR 1.26 (0.90–1.77)Body mass indexOR 1.96 (1.41–2.71)PLMI mean5–15>15–30>30OR 1.50 (1.03–2.19)OR 1.48 (0.94–2.35)OR 2.26 (1.28–3.99)PLMI mean >5OR 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 statusBillars L, et al. Sleep 2007;30(Abstract Supplement)A297. Abstract #0869.3333
42NFLE: clinical profile Age at onset yrsclusters of nocturnal short (< 60 s) motor seizures (NREM), sometimes prolongeddystonic-dyskinetic movements with tonic posture, complex motor activities (wandering, pelvic thrusting) or simple repetitive gesturesabrupt, stereotypic and intraindividually repetitiveabsence of ictal or interictal EEG abnormalities (rare frontal foci)
43Rem 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
45Some clinical-PSG aspects of RBD (Ferini-Strambi et al, 2005) M/F: 9/1Age of onset: 52.6 16 yrsAge at presentation: 59.3 15 yrsRarely children and adolescent onsetAltered dream process or enacting behaviors92%PLMS 63% (legs/arms) % SWS for age (84%)(% st 3-4 NREM = 25 6)