Sleep Flashcards
Features of NREM
Increased parasympathetic tone
Decreased metabolism.
Decreased muscle tone relative to wakefulness.
Decreased responsiveness
Growth hormone and prolactin released during slow wave sleep
Features of REM sleep
Features of REM Sleep
TONIC
• Desynchronized EEG
• EMG atonia
• poikilothermia
• peniletumescence
• increasedcerebral blood flow
PHASIC
• rapid eye movements
• middle ear muscle
activity
• muscle twitches
• cardiopulmonary variability
• Pontine-Geniculo- Occipital (PGO) waves
Wake promoting systems
The tendency to go to sleep and wake earlier in older individuals is explained by:
Advancement of the phase of the circadian clock with age
Circadian clocks of blind patients (due to degeneration of rods/cones)
Can be entrained by light
Normal sleep physiology summary
Normal sleep physiology: Summary
During health, sleep is regulated by circadian and homeostatic processes.
The circadian regulation of sleep is relatively well-understood both at the level of the light input pathways and of the core cellular oscillator. Homeostatic regulation of sleep is poorly-understood.
Multiple wake systems are partially redundant but may each serve unique functions. i.e. not all wake is the same. Remember: monoamines plus ACh, Glutamate, and Orexin.
NREM sleep control has two identified systems (VLPO and PFZ), but there are inputs to this system (e.g. Basal forebrain)
REM sleep is not simply a reduction in monoaminergic tone, but an active inhibitory process in the pons. We are (mostly) paralyzed during REM sleep.
The entire system is delicate and disturbed by medications, stressors/illness, and age.
Sleep is required for life and is observed in all animals yet its core function remains a mystery.
SCN and the pineal gland
The suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock. It is located above the optic chiasm.
The SCN regulates the pineal gland, an endocrine gland located posterior to the thalamus.
The pineal gland secretes melatonin during darkness. Melatonin in humans is weakly sleep-promoting.
Blue light suppresses melatonin production.
Melatonin
Melatonin secretion begins 2 to 3 hours before bed.
Melatonin feeds back to (weakly) to reset the circadian clock through melatonin receptors in the SCN.
– Ramelteon & Tasimelteon: melatonin receptor agonists.
– Beta-blockers can suppress melatonin release
Melatonin taken in the afternoon can phase-advance the internal clock and can be used as a sleep aid.
Neural mechanisms governing wakefulness
Monoamines: histamine, serotonin, NE, dopamine
How is wakefulness turned off?
Sleep regulation
1) Circadian clock - cyclical with nadir (based around core body temperature) occurring in early morning
2) Homeostatic process - builds up throughout the day
Normal circadian period and changes with age
Period is close to 24 hours, with variations across individuals and an average slightly >24 hrs.
Aged individuals do not change their circadian clock period—they only advance the phase of the rhythm
When are strokes most likely to occur?
6 AM to noon
Components of a circadian rhythm - the regulator
A canonical model of the mammalian circadian clock. The mammalian circadian clock consists of the central oscillator, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and peripheral oscillators present in virtually all cell types. Light activates a specific group of photoreceptors in the retina that are connected to the central SCN clock, which synchronizes and entrains peripheral circadian clock via neural and endocrine pathways. At the molecular level, CLOCK and BMAL1 heterodimers activate transcription of Period (Per) and Cryptochrome (Cry) genes. PER and CRY proteins in turn inhibit their own expression by repressing CLOCK/BMAL1 activity. This negative feedback loop, with additional post-translational modifications, generates ~24-h oscillations of clock protein levels and activity, which is translated into circadian behavior and physiology. The molecular mechanisms of rhythm generation are cell autonomous and highly conserved in the SCN (the central clock) and peripheral cells (the peripheral clocks)
Components of a circadian rhythm - input
SCN and melatonin
OSA
• Affects 2-4% of middle-aged adults. Twice more common in men.
• Mechanism: intermittent collapse of upper airway during sleep. Associated with obesity.
• Untreated OSA associated with increased risk of stroke and heart disease
• Untreated OSA can worsen seizure control
• Morning headaches can be associated with OSA
• Primary treatment is with continuous positive airway pressure (CPAP).
• Alternative treatments: (1) An oral appliance. (2) hypoglossal nerve stimulator.
OSA vs CSA vs Mixed
Central sleep apnea syndromes
Primary or idiopathic central apnea
Cheyne-Stokes respiration
– Seen in patients with congestive heart failure
High-altitude periodic breathing
Central hypoventilation:
– may be congenital or acquired
– reflects brainstem pathology
Narcolepsy
Hypersomnolence
Cataplexy
Hypnogogic and hypnopompic hallucinations
Sleep paralysis
Impaired sleep quality
Dx:
- Polysomnogram (Primary role is to exclude other causes for sleepiness):
- Multiple Sleep Latency Test (Five 20-minute nap opportunities): Mean sleep latency < 8 minutes, REM sleep in 2 or more naps (“sleep-onset REM Periods”).
Narcolepsy: Pathophysiology
A dissociated state in which normal sleep architecture is disrupted
REM-related phenomena intrude into wakefulness
Genetic predisposition: class II HLA type, DQB1*0602 in 95%
Hypocretin (orexin) neuron are eliminated. Therefore, hypocretin is absent in the CSF
Autoimmune etiology is suspected
– HLA linkage
– Association with flu vaccine in Northern Europe in 2010 – Association with polymorphisms in T cell receptor
Narcolepsy: Treatment
Hypersomnolence:
• naps
• conventionalstimulants(amphetamineclass) • modafinil and armodafinil
• sodiumoxybate
Cataplexy:
• sodiumoxybate
• TCAs(e.g.protriptyline)*
• SSRIs and SNRIs *off label
Episodic hypersomnolence
Kleine-Levin Syndrome
Basilar Migraine
Menses-related
Psychogenic
Kleine-Levin syndrome
Recurrent episodes of sleepiness lasting days to weeks
+/- Increased appetite
+/- Behavioral change
Primarily affects adolescent males
Etiology unknown but possibly autoimmune
No clearly effective treatment
Circadian rhythm sleep-wake disorders
Alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm to the external environment
There must be functional impairment (occupational, social, or other).
Disorder must not be better explained by another primary sleep disorder (e.g. narcolepsy, obstructive sleep apnea).
Diagnostic modalities for circadian rhythm sleep-wake disorders
Morning-evening questionnaires
Patient sleep logs
Actigraphy (similar to Fitbit)
Measurement of phase markers such as dim light melatonin onset (not yet used clinically)
Overnight PSG is rarely helpful
Insomnia
Difficulty initiating or maintaining sleep
Fatal Familial Insomnia. Extremely rare.
Restless legs/Periodic limb movements
Circadian rhythm disorders
Mood disorders
Secondary to other medical disorders or medication effect
Psychophysiologic (conditioned) insomnia
Fatal Familial Insomnia
Progressive insomnia
Progressive loss of sleep architecture
Dysautonomia
Ataxia and myoclonus
Atrophy of anterior and dorsomedial nuclei of thalamus
Mutation in codon 178 of cellular prion precursor protein
Restless legs syndrome (RLS)
An awake sensory phenomenon with a volitional motor response
Limb dysesthesias which produce an irresistable urge to move
Symptoms exacerbated by rest and relieved by voluntary movement
Symptoms worse in the evening and at night
Iron deficiency
– Can be pre-anemic.
– Always check Ferritin level!
Pregnancy (11-33% of pregnant females)
Chronic Renal Failure (17-62% of CRF pts)
Drug effect: lithium, neuroleptics, antidepressants, caffeine, amphetamines
May reflect impaired central dopaminergic transmission and reduced supra-spinal inhibition
• This impairment may be caused by decreased availability of iron in the brain
Non-Pharmacologic for mild RLS – Counter-stimulation, stretching.
Dopamine agonists (beware of augmentation) – pramipexole and ropinirole (doses are much lower than those needed to treat Parkinson’s Disease), rotigotine transdermal system (for severe RLS)
Gabapentin enacarbil extended release tablets.
Opiates (off label)
I =ron repletion (consider if ferritin < 50 mcg/ml even if serum iron is normal)
Periodic Limb Movements of Sleep
An involuntary sleep-related motor phenomenon. Not always pathological.
Stereotyped limb movements during sleep • Legs > > arms involved
Leg movements resemble triple flexion
Occur at 20-40 s intervals (range: 5-90 s)
Duration 0.5-10 s
+/- associated with arousal
PLM Disorder
An involuntary sleep-related motor phenomenon associated with arousals and sleep disruption
NREM sleep parasomnias
Primarily disorders of arousal that include:
Confusional arousals
Sleep walking (may include other behaviors)
Sleep terrors
These:
Originate in slow wave sleep
Lack of recall
Often positive family history
Common in childhood
Exacerbation by ETOH and by sleep loss
REM-sleep parasomnias
Recurrent nightmares
– Image Rehearsal Therapy is effective
– When associated with PTSD, can be treated with Prazosin
REM Sleep Behavior Disorder (RBD)
Sleep Paralysis
– Can occur in normals
– Rarely need to treat.
RBD
A dissociated state characterized by:
Violent dream-enacting behavior by hx or PSG
Increased tonic or phasic EMG in REM sleep
Absence of epileptiform activity
Male»_space;female
Mean age onset 52 ± 17 years
Long prodrome common (mean22±16years)
Response to clonazepam (0.5 to 2mg)
A high percentage of patients with RBD later develop a neurodegenerative disorder
– Parkinson’s Disease
– Lewy Body Dementia – Multi-system Atrophy
SCA3 (Machado Joseph Disease)
Sleep and epilepsy
Sleep and Epilepsy
Seizures occur in NREM»_space; REM
Specific sleep-related epilepsies include:
– Benign Rolandic Epilepsy (childhood syndrome)
– Autosomal Dominant Nocturnal Frontal Lobe Epilepsy: Treated with carbamazepine
– Electrical Status Epilepticus of Sleep
