BMS200 wk9 sleep physiology.pdf

BMS 200 – Sleep, part 1 Physiology of Sleep and Selected Sleep Disorders Objectives Describe the relevant neuroanatomy in the context of physiology and regulation of sleep and wake states Integrate the biochemistry of melatonin synthesis with environmental factors such as light exposure, and o...

BMS 200 – Sleep, part 1 Physiology of Sleep and Selected Sleep Disorders Objectives Describe the relevant neuroanatomy in the context of physiology and regulation of sleep and wake states Integrate the biochemistry of melatonin synthesis with environmental factors such as light exposure, and other physiological factors such as external temperature Define sleep architecture, including stages of sleep, REM sleep, and the different brain waves that characterize them Describe the etiology and pathophysiology of sleep apnea Describe the etiology and pathophysiology of narcolepsy and cataplexy Describe the etiology and pathophysiology of restless leg syndrome Describe the pathophysiology of parasomnia's including night terrors and sleepwalking What is sleep, and why does it happen? Surprisingly difficult question to answer, despite the fact it constitutes 1/3 of our lives ▪ Disruption of sleep increases the risk of stroke, hypertension, and coronary artery disease - Disrupted breathing during sleep elevates these risks ▪ Only about 30% of adults in NA report getting enough sleep, and 50% report that their sleep is disturbed ▪ Sleep deprivation degrades cognitive performance, and deeper (Stage III/IV, or N3 sleep) sleep seems to be more critical Experimentally, adults can be deprived of REM sleep with little in the way of psychologic consequences  How do we measure sleep… or wakefulness? Polysomnography is used to measure the states of wakefulness → sleep ▪ EEG (electroencephalogram) – surface electrodes that are attached to the skull ▪ EMG (electromyogram) – electrodes attached to skeletal muscle – face and legs, usually ▪ EOG (electrooculogram) – electrodes https://en.wikipedia.org/wi measure eye movements ki/File:Polysomnography_te ster.jpg ▪ Often ECGs and pulse oximeters will be attached as well, to determine oxygenation and cardiac function  What does an EEG measure? Your cortex is organized in 6 major layers – the largest and one of the most prevalent cells in those layers is the pyramidal cell * ▪ Apical dendrites are localized closest to the skull ▪ The axon is deeper down, and travels to a variety of targets including the white matter and descending tracts Since the very large dendrites are closest to the electrode, measurements usually reflect differences in potential between the seem i dendrite and cell body… - ▪ They don’t seem to directly measure action potentials EEGs and “states of consciousness” EEGs leads measure two major things in the underlying cortex ▪ Frequency of potentials (rhythms or waves, in Hz) ▪ Size of waves (in uV) When you have your eyes closed and your mind wanders, you have waves that are known as the alpha rhythm ▪ 8-13 Hz, “medium amplitude” waves When you open your eyes and are wide awake, then you exhibit what is known as the beta rhythm ▪ 13 – 30 Hz, “low amplitude” waves When awake, the ECG waves don’t usually show regular waves and look “random” - REM sleep looks “random” too When sleeping, regular patterns/waveforms can be discerned ▪ Known as synchronized sleep (awake/REM is known as dys- synchronized)  EEGs and “states of consciousness” EEG records showing the alpha and beta rhythms. When attention is focused on something, the 8–13 Hz alpha rhythm is replaced by an irregular 13–30 Hz low- voltage activity, the beta rhythm Known as alpha block, 2 arousal, or the alerting response EEG waves during the awake state are smaller in amplitude than those during sleep – fewer cortical neurons are firing in a synchronized fashion Polysomnographs and Sleep Stages Sleep stages are defined by their findings on polysomnography (PSG) Stage 1 sleep – transition from wakefulness to sleep * ▪ Low-amplitude, low frequency EEG trace known as theta - Are rhythm (4-7 Hz) Note – ‘”theta” just refers to frequency Theta rhythms can be found in states of wakefulness during certain activities as well ▪ Activity present on the EMG and EOG – eye movements are slow and rolling ▪ Known as N1 sleep in more modern classification systems Polysomnographs and Sleep Stages Sleep stages are defined by their findings on polysomnography (PSG) Stage 2 sleep – two major EEG features: ▪ K-complexes – high-amplitude spikes that appear intermittently ▪ Sleep spindles – 7 – 15 Hz groups of waves ▪ Subject is sleeping lightly and can be easily awakened ▪ Limited to no eye movement, activity is present on EMG ▪ Known as N2 sleep in more modern classification systems K Sleep complex spindle Polysomnographs and Sleep Stages Stage 3 & 4 sleep – EEG waves become less frequent and larger amplitude * ▪ These waves are known as delta waves D ▪ Frequency is 0.5 – 4 Hz, and the waves are large in stage 3, and become even larger amplitude in stage 4 ▪ Subject is in deep sleep and is D difficult to awaken ▪ Eye movements are minimal – fluctuations here represent underlying frontal lobe activity ▪ Together, stage 3 and 4 sleep are known as N3 sleep E Polysomnographs and Sleep Stages REM (rapid eye movement) sleep ▪ Unique activity on the PSG: Bursts of rapid eye movements on the EOG EMG “flatline” – almost no MSK movement (other than eye movements) Low amplitude, higher frequency EEG which resembles theta rhythm in N1 – activity is lower amplitude m an and not synchronized - ▪ Known as R sleep in more modern classifications ▪ Subjects are easily awakened from REM, and dreams are usually recalled upon awakening Movements during sleep Electromyograms during N1 – N3 sleep register a number of movements – often the electrodes are placed on the jaw and the legs ▪ Eye movements are fairly limited during N sleep, except for N1, the transition from wakefulness → sleep ▪ N1 – N3 sleep often involves larger movements that include the axial muscles – i.e. turning over to the other side, etc. During REM sleep, descending connections from REM-on neurons (more later) activate spinal inhibitory neurons that use GABA as a neurotransmitter ▪ This is why those in REM sleep are effectively paralyzed – very few movements, other than the odd finger- or toe-twitch EEG waves and sleep The large delta waves seen during N3 sleep are due to oscillations in activity between the thalamus and - - the cortex ▪ The source of the waves in N1 and N2 sleep aren’t as well known During REM sleep, the electrical activity occurs in the cortical association areas and is not - - ->synchronized ▪ Often don’t involve frontal “logic” areas, so this may offer a simple explanation as to why dreams are bizarre in nature Sleep architecture Sleep architecture refers to how a person progresses through each stage of sleep at night ▪ How long is spent in 53 each stage ▪ How often and when each stage is arrived at ▪ How often a patient awakens Sleep architecture changes throughout the lifespan The first sleep period is the longest – the rest tend to last 90 – 110 minutes  REM Sleep architecture ↓ Healthy young adults and children usually get most deep sleep (N3) early, soon after falling asleep We usually progress through the stages in an orderly sequence, though sometimes the transition through N1 and N2 sleep is very quick We never go from wakefulness directly to REM (red bar) ▪ We arrive at REM after “ascending” through deeper levels of sleep, usually N3 but sometimes N2 Sleep architecture Most REM sleep occurs near the end of a sleep session Elderly subjects have much fewer and shorter periods of N3 sleep, and more frequent awakenings Young children spend a lot of time in N3 and REM ▪ Almost 50% each in neonates ▪ steadily declines with age until ~ 25% each in young adults Sleep EEG Other PSG info General Features Lifespan Stage features Theta rhythm, 4 Rolling eye Just transitioning into sleep, None notable -7 Hz movements, easily wakened, may seem I (N1) some muscle somewhat awake but no short- activity term memory Theta with Limited eye Sleep is still light but more With age this K complexes + movement, some difficult to awaken than N1 stage occupies II (N2) sleep spindles MSK movement more of the sleep cycle than N3 Appearance of Limited eye Subject is very difficult to Children – 30 – III (N3) delta waves, 0.5 movement, some awaken and will be disoriented. 40% of cycle – 4 Hz MSK movement Sometimes dreams reported. Adults - ~ 25% More N3 early in the sleep Elderly – very little Bigger, slower session, less later IV (N3) delta waves Dys- Bursts of eye Subject is easy to awaken, and Children - > 25% synchronized movements, often will report dream content. Adults - ~ 25% REM theta-like almost no MSK More REM late in the sleep Elderly - < 25%, (R) movement session, less early on. Need to often very little be in N2 or N3 prior to entering REM  How are sleep-wake states regulated? In general, there seems to be an arousal system (green circles) that keeps us awake - The arousal system seems to “open the gate” of the thalamus and allow input from the outside world to the cortex The arousal system also communicates widely to hypothalamic areas that regulate sleep cycles as well as to the cortex in general  How are sleep-wake states regulated? Major components of the arousal system include brainstem nuclei that extend mostly through the midbrain and pons (lots of green circles) Locus ceruleus - norepinephrine Raphe nucleus - serotonin Tuberomamillary body- histamine Acetylcholine has multiple nuclei in the brainstem that are important in arousal Periaqueductal gray - dopamine  How are sleep-wake states regulated? A nucleus in the - - hypothalamus – the ventrolateral pre-optic nucleus (VLPO) seems to be one of the major sleep- promoting nuclei S like GABA and galanin 31 ▪ Releases inhibitory NTs REM sleep is likely regulated differently – in the brainstem there are “REM-on” (lateral pontine areas) and “REM-off” groups (pons portion of the locus ceruleus)  How are sleep-wake states regulated? The suprachiasmatic nucleus (SCN): Communicates with the retina Is the most likely “site” of our circadian rhythm ▪ Without light/dark stimulation, we have a rhythm that lasts just a little over 24 hours Responsible for “entraining” our circadian rhythm based on light and dark information Communicates indirectly with arousal systems and sleep- inducing centers  How are sleep-wake states regulated? Finally, there are the “stabilizing” nuclei The lateral hypothalamus has a population of neurons that secrete two major chemicals: ▪ Orexin – projects to both - the arousal systems and to - the VLPO - > - major sleep-promoting nuclei ▪ Melanin-concentrating hormone (MCH) – also projects - to arousal systems Orexin and MCH are important for keeping a subject in a “stable” sleep state A more detailed image - arousal systems and VLPO projections Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback, Patrick M. Fuller, Joshua J. Gooley, and Clifford B. Saper, Journal of Biological Rhythms 2006 21:6, 482-493 See notes for details  Neurophysiology of Sleep General model: We don’t want any “halfway between awake and asleep” situations ▪ Therefore the sleep centers will directly and indirectly inhibit the arousal centers ▪ The arousal centers also directly inhibit the sleep centers There are two drivers that make -3 us sleepy ▪ The circadian rhythm that tells us it’s bedtime ▪ The homeostatic signal that builds the longer we go without sleep  Neurophysiology of Sleep What pushes us towards wakefulness? Stimuli – whether it’s circadian or homeostatic or some other stimulus in general – activate our arousal systems ▪ In this diagram they’ve included the tuberomammillary nucleus (histaminergic), the locus coeruleus (noradrenergic), and the raphe nuclei (serotonergic) 2 The arousal system directly inhibits the VLPO nuclei seem i Orexin activity is increased – and orexin also activates the arousal nuclei * -S inhibited Orexin + inhibition of the VLPO → a durable waking * state Q  Neurophysiology of Sleep What pushes us towards sleep? Stimuli – whether it’s circadian or homeostatic activate the VLPO ▪ The VLPO directly inhibits both the arousal systems and orexin release from the lateral hypothalamus Since orexin release from the lateral hypothalamus is silenced (orexin stimulates the arousal system) AND increased activity of the VLPO inhibits the arousal system directly, then a durable sleep state is maintained The thalamocortical I inhibited oscillations that generate EEG waves are also turned ↳ back on I A more detailed image - arousal systems and VLPO projections Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback, Patrick M. Fuller, Joshua J. Gooley, and Clifford B. Saper, Journal of Biological Rhythms 2006 21:6, 482-493 See notes for details Neurophysiology of Sleep Since the sleep-inducing and the arousal groups of neurons inhibit each other, we’re usually either sleeping or awake, not in-between - ▪ Like a light-switch – this is known as a “flip-flop switch” ▪ MCH release from the lateral hypothalamus predominates during REM sleep – it inhibits the - monaminergic arousal system (keeps you asleep during Freem REM) Neurophysiology of Sleep This is the case for REM sleep as well ▪ REM-on neurons inhibit the REM-off neurons, and REM-off neurons inhibit REM-on neurons ▪ REM-on neurons project widely and are stimulated by cholinergic inputs cause the previously-mentioned inhibition of movements as well as the brain activity in the association areas and limited parts of the forebrain ▪ REM-off neurons tend to be stimulated by norepinephrine and serotonin inputs AND they are also stimulated by orexin release from the lateral hypothalamus REM, Non-REM, and Wakefulness model See description below A brief segue – melatonin and circadian rhythms Melatonin is produced in the pineal gland, a tiny, pea-sized men - portion of the epithalamus right above the colliculi in the - midbrain attached to the roof of the 3rd ventricle (no BBB)* - ▪ It is indirectly stimulated to produce melatonin during periods of darkness Melatonin is an interesting metabolite of serotonin (which a.a.?) that may have other Tryptophan functions other than entrainment of circadian rhythms https://upload.wikimedia.org/wikipedia/commons/6/6b/Illu_pituitary_pineal_glands.jpg  Regulation of melatonin secretion In the absence of light → retinohypothalamic fibres relay “dark info” to the SCN → lifting of the inhibition of the PVN by the SCN In the absence of light, the PVN then activates the sympathetic nervous system: ▪ Intermediolateral horn cells excite post-ganglionic neurons in the superior cervical ganglion &NE released ▪ NE is released at the - pineal gland → Superior melatonin synthesis cervical ganglion and release  Regulation of melatonin secretion Serotonin is synthesized in the pineal gland With catecholamine stimulation (beta1- receptors) the activity Stimulation from and production of NE = more AANAT AANAT and the = more melatonin secretion availability of serotonin increases → more ~* melatonin synthesized With withdrawal of catecholamines, AANAT is degraded by proteosomes What does melatonin do, sleep-wise? Although the SCN has its own endogenous cycle that is just over 24 hours long, it needs to be entrained ▪ The retinohypothalamic fibres can relay light information and “synch up” the SCN to day/night periods ▪ However, melatonin also seems to have a role, and activation of melatonin receptors (most likely MT-2 type receptors are more important) helps the entrainment of the SCN to light- dark cycles Melatonin can both decrease sleep latency and increase the amount of time that a subject spends sleeping ▪ Thought that MT-1 receptors decrease sleep latency and MT- 2 receptors help maintain sleep for longer (may be oversimplified) Melatonin secretion entrains a number of physiologic/endocrinologic cycles to day-night cycles: ▪ Cortisol secretion and TSH secretion ▪ Core body temperature ▪ Heart rate variability Melatonin plays a key role in the entrainment of these circadian rhythms to light- dark stimuli https://www.ncbi.nlm.nih.gov/books/NBK550972/#:~:text=The%20main%20function%20o f%20the,secretion%20of%20the%20hormone%20melatonin. Homeostatic and Allostatic Regulators of Sleep We now are aware of melatonin and the SCN as important circadian regulators of sleep-wake cycles However, the longer we go without sleep, the more we desire it and the more likely we are to lapse into N1 (nod off) when we close our eyes ▪ This is known as the homeostatic drive for sleep ▪ Although knowledge is still developing, it may be that extracellular adenosine build-up during wakefulness may be responsible for the homeostatic drive Caffeine is an adenosine receptor (A2a) antagonist A1 receptors are thought to inhibit arousal pathways, A2a are thought to facilitate sleep- promoting pathways Homeostatic and Allostatic Regulators of Sleep Allostasis = the response to stressors (physical, psychologic) that cannot be adequately managed by homeostatic mechanisms ▪ People who endure psychologic stress have difficulty sleeping (no surprise there) ▪ The ascending monaminergic arousal system is excessively activated in these situations This is of course adaptive if it keeps you from falling asleep in a stressful situation, but impairs sleep quality over long - periods of time - Common disorders of sleep Narcolepsy Restless legs syndrome & periodic limb movement disorder Obstructive sleep apnea Selected parasomnias Narcolepsy Thought to affect 1 in 2000 people ▪ Likely underdiagnosed, so could be higher Characterized by the following features: ▪ Excessive daytime sleepiness ▪ Symptoms that suggest intrusion of REM sleep characteristics into wakefulness s Cataplexy (in > 50% of sufferers) Sudden and temporary loss of muscle tone Sleep paralysis Dream-like hallucinations while still awake Pathogenesis: ▪ 50% of those with narcolepsy & cataplexy have a clear cause – loss of orexinergic neurons ▪ Pathogenesis is less clear for those without cataplexy Narcolepsy – Clinical Features Cataplexy = sudden muscle weakness without a loss of consciousness ▪ This can be mild – partial weakness of the face or neck ▪ Can be severe – individuals collapse to the ground for minutes, immobile ▪ Often precipitated by an emotional response to something – laughing at a good joke, for example ▪ Very diagnostically useful when present – almost no other * A disease does this Excerpt from Harrison’s: ▪ “Many disorders can cause feelings of weakness, but with true cataplexy patients will describe definite functional weakness (e.g., slurred speech, dropping a cup, slumping into a chair) that has consistent emotional triggers such as laughing at a joke, happy surprise at unexpectedly seeing a friend, or intense anger.” Video example: https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/MultimediaPlayer.aspx?MultimediaID=20083904 Narcolepsy – Clinical Features Excessive daytime sleepiness is kind of an understatement ▪ Several times a day, usually after eating or when bored, the affected person falls asleep – naps usually last 15 minutes or less, and the person is easily aroused ▪ The napping is pretty much irresistible, and it happens 2 – 6 times/day ▪ Automatic behaviour can occur – patient does routine tasks, kind of looks awake, but doesn’t respond appropriately to questions – during attacks The sleep attacks make driving exceptionally hazardous Patients who have other sleep disorders can have a similar presentation, but the napping is usually not as irresistible as in narcolepsy Narcolepsy – Clinical Features Sleep paralysis and hallucinations around the time of falling asleep (hypnagogic hallucinations) or upon awakening (hypnopompic hallucinations) are actually common ▪ Occur in 20% of the general population on an occasional basis ▪ However, usually more frequent in those with narcolepsy Sleep paralysis occurs on awakening, and is often terrifying ▪ Patients can’t move at all for minutes after awakening, some feel that they can’t breathe ▪ Outside stimuli (touch or someone walking into a room) can help terminate the episode Narcolepsy - Pathogenesis Easy to see how loss of orexinergic neurons in the lateral hypothalamus can lead to almost every symptom See poor sleep quality on next slide Rapid transitions into and out of sleep states with “blurring of the borders” between REM and wakefulness Orexin stimulates arousal systems & stabilizes your sleep  Narcolepsy – sleep quality The healthy individual has a long period of NREM sleep before entering REM sleep Narcoleptic enters rapid eye movement (REM) sleep quickly at night and has moderately fragmented sleep During the day, the healthy subject stays awake from 8:00 A.M. until midnight Patient with narcolepsy dozes off frequently, with many daytime naps that include REM sleep Narcolepsy – Pathogenesis and Treatment Why does a patient with narcolepsy lose orexinergic neurons? ▪ Usually autoimmune - HLA DQB1*06:02 (an MHC II gene) is found in > 90% of people with narcolepsy with cataplexy ▪ Molecular mimicry of orexin with common respiratory tract pathogens, including viral influenza and streptococcal species ▪ Narcolepsy with cataplexy is known as Type I narcolepsy Treatment usually involves antidepressants that increase noradrenergic or serotonergic tone – these NTs stimulate - - REM-off neurons ▪ Methylphenidate or modafinil increase the availability of dopamine at the synapse – this helps stimulate the “arousal nuclei” in the brain stem * - - RLS/PLMD Restless legs syndrome (RLS) – hard to describe, unpleasant, irritating compulsion to move the legs that is triggered by rest, drowsiness, or sleep ▪ Usually interferes with sleep – many report daytime sleepiness due to interruption of sleep Makes it difficult to fall asleep – the symptoms only happen when the subject is awake ▪ Very common – 5 – 10% of adults, more common in women and in older people Periodic limb movement disorder (PLMD) occurs during sleep – movements (often large movements) that frequently involve the legs ▪ Looks like kicking movements ▪ Very common, often occurs with RLS, and is thought to have a similar pathogenesis RLS/PLMD Pathogenesis is poorly-understood, but knowledge is developing ▪ Strongly associated with iron deficiency, but most patients with RLS do not have peripheral signs of iron deficiency (low ferritin) or anemia ▪ However, studies seem to indicate that deficiency in iron content in the brain is a common finding in RLS patients (established through sampling CSF) ▪ Also seems to associated with abnormalities in dopaminergic signaling – MRI studies suggest that iron transport is particularly impaired in dopaminergic areas such as the substantia nigra RLS/PLMD Pathogenesis is poorly-understood, but knowledge is developing cont… ▪ Abnormalities in iron transport/metabolism may impact a range of dopamine-related processes, including synthesis (tyrosine hydroxylase) and changes in dopamine receptors and transporters ▪ Although overall dopamine metabolites are increased in c the CSF, effective treatment involves dopamine agonists ▪ Researchers hypothesize that excessive dopamine activity in the morning and inadequate dopamine activity at night may be the cause RLS/PLMD Movement disorders are the usual clinical consequence of issues that impact the basal ganglia and substantia nigra (extrapyramidal system) ▪ The extrapyramidal system is dependent on dopaminergic transmission ▪ However, how dopamine neurochemistry is related to the discomfort of RLS or the movements of PLMD is not fully understood ▪ The circadian rhythm of dopamine release from midbrain structures that impact movement (lower at night) seems to be exaggerated in those that suffer RLS Obstructive Sleep Apnea What is it? How is it diagnosed? ▪ Nocturnal findings – 5 or more episodes of obstructive apnea or hypopnea during one hour of sleep Apnea = cessation of airflow for ≥ 10 seconds during sleep, despite respiratory effort Hypopnea = a ≥ 30% reduction in airflow for at least 10 seconds during sleep that is accompanied oxygen desaturation or waking Often those with severe OSA have > 15 episodes/hour ▪ Often the respiratory nocturnal symptoms are accompanied by gasping, snoring, choking, or waking throughout the night ▪ Nocturnal findings are diagnosed during a sleep study – could be polysomnography or less complicated methods Obstructive Sleep Apnea What is it? How is it diagnosed? ▪ Daytime symptoms Excessive daytime sleepiness – difficulty maintaining alertness or involuntary periods of napping ▪ Can actually resemble narcolepsy if sleep deprivation is severe (but no cataplexy, and less likely to experience sleep-associated hallucinations or sleep paralysis) Reports of an unsatisfying or unrefreshing sleep Fatigue and morning headaches Difficulty concentrating, irritability, mood disturbances May also report dry mouth, heartburn, nocturia, and diaphoresis in the upper body  OSA - Pathogenesis Inspiration results in negative pressures within the pharynx ▪ We rely on pharyngeal dilator muscles to keep our upper pharyngeal airway open ▪ As neuromuscular tone decreases during sleep, the negative pressure causes the pharyngeal structures to collapse ▪ Sites of collapse include: Soft palate (most common) Tongue base Lateral pharyngeal walls and epiglottis ▪ Unsurprisingly, may be most severe during REM sleep OSA - Pathogenesis Obesity and OSA Excess adiposity, especially in the upper body (androgenic distribution) is strongly implicated ▪ Upper airway fat narrows the pharyngeal lumen ▪ Reduces chest wall compliance (the ease of expanding the chest wall) and can decrease lung volumes Result is that the lungs/chest wall don’t “pull” the upper airway structures downwards as well during inspiration (loss of caudal traction on upper airway structures) ▪ Estimated that 40 – 60% of OSA cases are due to excess weight – 10% weight gain is associated with a > 30% increase in the AHI, a scoring system that ranks apnea/hypopnea while breathing OSA - Pathogenesis Other factors in OSA pathogenesis Smaller or more collapsible pharyngeal lumen – collapses more easily during sleep, and requires more neuromuscular activation to keep patent ▪ Can be narrowed due to enlargement of tongue, palate, uvula ▪ Can be due to smaller jaws or retrognathia (mandible is positioned more posterior) ▪ Lower lung volumes outside of obesity exacerbate the problem (less caudal traction again) ▪ Septal deviation or nasal polyps reduce the pressures that promote air flow further down in the pharynx As well, poor nasal airflow → mouth breathing → tongue falls posteriorly and obstructs the pharynx  OSA - Pathogenesis Note the seal that the tongue makes on the soft palate with the mouth closed ▪ When the mouth is open, the tongue is free to fall back and seal the upper airway ▪ Nasal obstruction therefore complicates pharyngeal obstruction, even though the mouth may be open OSA - Pathogenesis Other factors in OSA pathogenesis Sensitivity to carbon dioxide concentrations in the bloodstream can also play a role ▪ As carbon dioxide in the bloodstream increases, ventilatory drive (mostly stimulated by medullary nuclei) also increases ▪ In those without OSA, increases in carbon dioxide concentration result in appropriate increases in ventilatory drive and stiffening of upper airway muscles → patent pharynx If that isn’t enough, then accumulation of carbon dioxide wakes us up ▪ In those with OSA, a low arousal threshold (hypersensitivity) to hypercarbia → awakening before increasing pharyngeal stiffness Can also cause fluctuations in ventilatory drive that result in periodic airway obstruction and inadequate pharyngeal muscle activation ▪ As well, a high arousal threshold could result in prolonged apneas - not waking up even though the airway is obstructed and significant hypercarbia is occurring OSA – Risk Factors & Pathogenesis Already mentioned ▪ variance in jaw size/structure, upper airway structure, larger tonsils (children with larger tonsils can have OSA) ▪ obesity, variations in ventilatory drive with hypercarbia Genetics – first degree relatives have double the risk of having OSA Male sex – more likely to have upper body obesity, longer pharynx (easier to collapse) Age – 5 – 15% prevalence in middle-aged adults, but > 20% in the elderly Associated with diabetes, hypertension, and atrial fibrillation ▪ Chicken or the egg?  OSA – Diagnostic Considerations Sleep history should include information from someone who has observed the patient sleeping, if possible Physical and further investigations should screen for: ▪ Hypertension, cardiac abnormalities (i.e. signs of CHF or atrial fibrillation) ▪ Oropharyngeal exam should look for causes of obstruction Especially nasal polyps, septal deviation, intra-oral findings as already discussed https://en.wikipedia.org/wiki/ FYI – higher Mallampati score (see Mallampati_score right) increases the risk of OSA  OSA – Diagnostic Considerations * Gold Standard for OSA diagnosis – polysomnogram * ▪ Home sleep tests are economical – they measure nasal air flow, abdominal/chest excursions during breathing, and pulse oximetry (at minimum) High rate of false negatives, and need to be confirmed with formal PSG Other testing – FYI ▪ More advanced cardiac testing (looking for atrial fibrillation, risk of CHF, evaluation of angina if present) ▪ Home BP monitoring ▪ Imaging (CT, MRI) or endoscopy of the upper airway Parasomnias Abnormal behaviours or experiences that arise from or occur during sleep ▪ Sleepwalking (Somnambulism) – automatic motor activities that occur during sleep Occur during N3 sleep, so tend to occur early I the evening Most common in children and adolescents No clear pathophysiology yet identified ▪ Sleep terrors – usually in young children – child awakens either screaming or moaning, and exhibits autonomic signs that indicate fear (also occurs during N3) Tachycardia, hyperventilation, sweating After the attack is over, the child does not remember anything beyond a (mildly) bad dream ▪ For both, - often can be avoided by ensuring adequate sleep Parasomnias REM sleep behaviour disorder – one of the few parasomnias that occur during REM sleep ▪ Quite unpleasant – individuals “act out” their dreams and often results in violent movements (punching, kicking) that can injure bed partners or the patient ▪ Prevalence increases with age – unfortunately those with REM sleep behaviour disorder usually develop neurodegenerative disorders after (i.e. Parkinson’s, Lewy body dementia) Seems to predict the development of these later diseases, not cause them ▪ Thought to be caused by neurodegeneration in the interneurons that cause paralysis during REM sleep ▪ See here for a video: https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/MultimediaPlayer.aspx?MultimediaID =20083906