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Narcolepsy and Excessive Daytime Sleepiness

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Narcolepsy and Excessive Daytime Sleepiness Paul Reading Consultant Neurologist I. How much sleep is needed? the additional importance of sleep “quality” II. Effects of acute sleep deprivation • sleepiness • neuro-behavioural • neuro-psychological • altered gene expression • neuro-toxicity? III. Likely effects of chronic sleep loss epidemiological evidence IV. Conclusions How much sleep is needed (and how much do we get) ? 6 hours for a man 7 hours for a woman 8 hours for a fool Napoleon “Sleep is a criminal waste of time, inherited from our cave days” Total sleep deprivation is fatal in rats Mechanism of death? - multi-organ failure - inflammatory markers ↑↑ - bacteraemia - wt loss despite ↑ food intake - thermoregulation ↓ - seizures Total Sleep Deprivation is it fatal in humans? Article from Psychological Review, 1859: “ A Chinese merchant had been convicted of murdering his wife and was sentenced to die by being deprived of sleep … The [three] police guards relieved each other every alternate hour, preventing him from sleep, night and day. He thus lived for nineteen days. At the commencement of the eighth day, his sufferings were so intense that he implored the authorities to grant him the blessed opportunity of being strangulated, guillotined, burned to death, drowned, garrotted, shot, quartered, blown up with gunpowder, or put to death in any conceivable way which their humanity or ferocity could invent. This will give a slight idea of the horrors of death from want of sleep ” Sleep duration and mortality chance of death within 6 yrs follow-up 1.5 n > 1 100 000 Men Kripke et al, 2002 1.4 Women 1.3 ~20% report 6 hours or less 1.2 hazard ratio hazard 1.1 1 3 4 5 6 7 8 9 ≥10 reported hours of sleep How much sleep is needed? Between 7 and 7.5 hrs for significant majority of adults “long and “short” sleepers actually quite rare note: Thatcher / Napoleon / Trump (~4h) v Einstein (~10h) Quality probably as important as quantity amount of deep SWS (>90 mins) particularly important other measures: “sleep efficiency”, “wake after sleep onset” REM more important for development / memory consolidation? Concept of widespread chronic “sleep debt” popular do we really sleep less than 100 years ago? (~ 6.8h v 8.2h) Sleep drive is primarily homeostatic (c.f. hunger and thirst) but circadian influences should not be ignored nadirs of alertness at 4am & 3pm are afternoon naps normal and / or beneficial? did we evolve to have a “two sleeps a night” strategy? Acute Sleep Deprivation sleepiness (subjective versus objective…) physical signs may be minimal : - yawning - “heavy/dark eyes” - slow blink rate pupillometry objective lab-based measure multiple sleep latency test (MSLT) mean latency usually >12 mins : ~3 mins if no sleep previous night Acute Sleep Deprivation “micro-sleeps” (“local sleep”) lapses/microsleeps (~3s) can occur with eyes closed or open note: inattention also due to increased distractibility when sleepy Acute Sleep Deprivation neuro-behavioural consequences Acute Sleep Deprivation neuro-behavioural consequences reaction times slower 90 minutes of sleep loss ≈ 10 years of normal aging sustained attention impaired, poor vigilance, frequent lapses note adverse effects on driving simulator Dawson & Reid (Nature 1997) How much sleep is needed? the psycho-motor vigilance test 0 14 0 14 PVT = psychomotor vigilance test 8 hrs/night 6 hrs/night 4 hrs/night data suggest increasing signs of sleepiness even with regular 6 hours of nocturnal sleep 0 hrs/night but subjective sleepiness ≠ objective sleepiness….. Van Dongen et al 2002 Sleep Acute Sleep Deprivation neuro-psychological consequences sleep “Disorders of arousal” e.g. sleep walking; deprivation Hypnic jerks WAKE Cataplexy; Sleep paralysis; Hallucinations; e.g. narcolepsy, PD Lucid dreaming NREM REM “overlap” syndromes or “ambiguous sleep” common in narcolepsy and some dementias (esp DLB) cf delirium Acute Sleep Deprivation neuro-psychological consequences “Hypo-frontality” perseveration/reduced flexibility Harrison and Horne 1999 impaired sense of humour Killgore et al 2006 increased risk taking Venkatraman et al 2007 poor moral judgement Killgore et al 2007 reduced “emotional intelligence” van der Helm et al 2010 negative mind set van der Helm and Walker 2010 adverse effects on “economic decisions” Anderson 2010 increased distractibility Anderson et al 2011 Acute Sleep Deprivation poor sense of humour impaired sense of humour after 24h sleep deprivation the Pittsburgh humor scale (Kilgore, Sleep 2006) Headline 1: Vet investigates failed panda mating Headline 2: Panda mating fails: vet takes over on PVT, vigilance performance decrement to 72% of baseline normalised after all stimulants humor appreciation drops by 1 SD after sleep deprivation only significant improvement after stimulants : visual joke appreciation on Modafinil 400mg interpreted as improved frontal lobe function Acute Sleep Deprivation reduced “emotional intelligence” • after 24h SD, “angry” & “happy” emotions less recognised seen more in women full recovery after sleep period Acute Sleep Deprivation impaired emotional processing sleep loss in medical residents amplified negative emotional consequences of disruptive daytime experiences while positive benefits of rewarding activities were blunted (Zohar 2005) on tests of emotional memory : MR scans show limbic areas overactive to negative stimuli > 1 night SD (Yoo 2007) . “hyper-limbic state” . due to loss of functional connectivity with PFC? similar to changes seen in depression? Acute Sleep Deprivation likely effects on decision making in “real world” Neurosci Biobehav Rev 2012 36 p2226-31 reviewed effects of extended wake (acute SD) on “real world” tasks: novelty, unexpected change, uncertainty with competing distractions dealing with unexpected events; increased distraction increased mistakes when shifting seen on mundane (driving) and rapidly between simple cognitive tasks complex tasks (baggage screening) (Couyoumdjian 2009) (Anderson 2013, Basner 2008) poor recognition of emotions; morning types especially less trustful affected by adverse (acute) (van der Helm 2010; effects of night shift Anderson 2010) (Groeger 2008) sudden waking during sleep poor decision making at night impairs military strategic decisions on/after night shift less risk averse (Horne 2011) medical staff and reduced learning politicians / diplomats about losses when gambling; “values” associated bank traders more impulsive with economic decision making (Venkatraman 2007 and visual reward altered Anderson 2011) (Libedinsky 2011) sleep deprivation biases stimulant drugs (cocaine…?) reduce towards pursuit of gain (greedy) sleepiness and improve alertness but do rather than avoidance of loss not improve impaired risk assessment (Venkatraman 2011) (Killgore 2011) Acute Sleep Deprivation functional brain imaging after 24hr SD : dorso-lateral prefrontal cortex is metabolically underactive during cognitive tasks: even if performance normal PFC & thalamus appear relatively overactive similar to normal old age, brain has to work “harder” (Drummond Nature 2000) Structural imaging after acute sleep deprivation recent evidence for significant white matter tract changes diffusion tensor imaging (DTI) shows H2O diffusion across membranes after 23h awake: significant ↓ in axial & mean diffusivity in many areas fronto-temporal cortex, brainstem, thalamus axial diffusivity axial diffusion changes correlate with poor subjective sleepiness 14 h 23 h awake awake Acute Sleep Deprivation effects on gene transcription Proc Natl Acad Sci USA 2013 Feb 25 chronic sleep restriction is associated with (& contributes to?) : diabetic risk, cardiovascular problems, cancer, mortality but precise (cellular) mechanism unknown • ~8% of genes have clear diurnal / circadian rhythmicity seen in brain, liver, blood normal subjects (n=26) gene expression (>22 000) analysed (blood) : 5.7 h sleep for 6 days v up to 10 h sleep for 6 days • 711 genes affected (up or down) by sleep restriction Chronic (partial) Sleep Deprivation population studies hypertension metabolic syndrome mortality↑ depression (chronic) lack of (“good”) sleep immunity↓ selected references : diabetes Cappuccio F et al. Sleep 2010;33:585-92 Cappucio F et al. Eur Heart J 2011;32:1484-92 Chaput JP et al. Diabetologia 2007;50:2298-304 cancer Lange T et al. J Immunol 2011;187:283-90 Spiegel et al. Ann Intern Med 2004;141:846-50 Sleep Loss and the Metabolic Syndrome sleep deprivation / insufficient sleep leptin ↓ brain glucose nocturnal GH sympathetic ghrelin ↑ utilisation ↓ evening cortisol ↑ activity ↑ hypocretin ↑ glucose insulin blood tolerance ↓ secretion ↓ pressure ↑ hunger ↑ insulin resistance ↑ cardiovascular weight gain / type 2 diabetes problems & obesity risk hypertension hypertension metabolic syndrome mortality↑ depression (chronic) lack of (“good”) sleep immunity↓ dementia diabetes “sleep is of the brain, cancer by the brain and for the brain” is reduced sleep (or prolonged “wake”) actually neurotoxic? Conclusions Most adults need at least 7 hrs of good quality sleep - an estimated 20% of population have insufficient sleep - a bigger public health issue than alcohol / drugs of abuse? Acute SD affects attention, vigilance, reaction times - the brain has to “work harder”, similar to normal aging - some brain functions ~preserved (e.g. procedural learning) Cognitive effects of SD reflect frontal lobe dysfunction - ventromedial prefrontal cortex particularly vulnerable - not easily reversible with stimulant drugs, even if more alert Critical decision making likely to be vulnerable if SD - perseveration, poor risk assessment, emotional processing↓ .
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