Sleep and Sleep Disorders

CHAPTER 16


Sleep and Sleep Disorders


      I.  Wakefulness and Sleep Overview


           A.  Arousal system has two main ascending pathways:


                 1.  Cholinergic neurons in the pedunculopontine and laterodorsal tegmentum → ventroposterior and mediodorsal nuclei of thalamus ← self-inhibits gamma-aminobutyric acid (GABA) in reticular nucleus (as GABA mediates sleep)


                 2.  Monoamine neurons


                      a.  Noradrenaline in locus ceruleus


                      b.  Serotonin in dorsal and medial raphe nuclei


                      c.  Glutamate in parabrachial nucleus


                      d.  Dopamine in periaqueductal gray nucleus


                      e.  Histamine in tuberomamillary nucleus → lateral thalamus (picking up orexin and glutamate) → basal forebrain and cerebral cortex


           B.  Sleep-promoting pathway:


                 1.  GABA and galanin from ventrolateral preoptic (VLPO) nucleus and GABA from median preoptic nucleus → inhibit arousal systems.


                 2.  VLPO important in sleep promotion


                 3.  Two separate systems are necessary to be able to switch completely from wakefulness to sleep (rather than have in-between states). Orexin stabilizes the flip-flop switch.


      II.  Basics of Sleep Stages


           A.  Sleep makeup: N1 = 5% to 10%, N2 = about 50%, N3 = 15% to 20%, rapid eye movement (REM) = 20%


           B.  Wake


                 1.  Mediated by arousal pathways


                 2.  Electroencephalogram (EEG) will show prominent rhythmic alpha in occipital channels with eyes closed and low-amplitude mixed-frequency (LAMF) with eyes open.


           C.  Non-REM (NREM) sleep (N1, N2, N3)


                 1.  VLPO and basal forebrain critical in initiating sleep


                 2.  In N1, alpha is replaced by LAMF; in N2, sleep spindles and K-complexes; in N3, delta.


           D.  REM


                 1.  Driven by the pons


                 2.  Pontine cholinergic neurons induce REM.


                 3.  Serotoninergic neurons suppress REM.


                 4.  Glutaminergic neurons in sublaterodorsal area induce atonia during REM.


                 5.  EEG: LAMF with sawtooth waves


                 6.  Polysomnography (PSG) findings in early life key points:


                      a.  At 26 weeks: will see trace discontinuans—independent activity over each hemisphere or hemispheric asynchrony


                      b.  At 37 weeks: will see trace alternans—short bursts of high-voltage mixed-frequency activity alternating with low-voltage mixed-frequency activity


                      c.  At 30 weeks: REMs


                      d.  At 2 months: sleep spindles


                      e.  At 4 to 6 months: K complexes


                 7.  Clinical correlates


                      a.  REM sleep behavior disorder can be caused by lesion of sublaterodorsal nucleus (REM atonia is lost). Remember that REM sleep behavior disorder (RBD) is associated with parkinsonian syndromes (often a precursor).


                      b.  Loss of orexin causes narcolepsy and incomplete switching of sleep states.


    III.  Circadian Rhythm Overview


           A.  The circadian system has three main components: a circadian pacemaker (the suprachiasmatic nucleus [SCN] in the anterior hypothalamus), input pathways (receive light and other stimuli), and output signals regulated by the SCN.


           B.  Light is the most important and powerful stimulus for regulating sleep cycles.


    IV.  Sleep Disorders


           A.  Insomnia


                 1.  Most common sleep disorder


                 2.  Defined as difficulty initiating, maintaining, or staying asleep despite adequate opportunity and environment for sleep; must also have at least one form of daytime impairment (fatigue, sleepiness, mood disorder, lack of concentration, etc.)


                 3.  Disorder of the wake system resulting in round-the-clock hyperarousal


                 4.  Increases risk of comorbid chronic health conditions


                 5.  Diagnosis: sleep history and sleep log; PSG not necessary unless insomnia is felt to be secondary to another sleep disorder (such as obstructive sleep apnea or periodic limb movements)


                 6.  Treatment (of primary insomnia): cognitive behavioral therapy +/– medications (benzodiazepine [BZD], non-BZD hypnotics, melatonin receptor agonist, or selective histamine receptor antagonist)


           B.  Circadian rhythm disorders


                 1.  Delayed sleep phase syndrome


                      a.  Go to bed late, wake up late


                      b.  Most common in teens and young adults


                      c.  Diagnosis by sleep history and sleep log +/– actigraphy


                      d.  Triggers: light exposure and stimulating activity in evening


                      e.  Treatment: first line is morning light exposure with evening melatonin. Light should be used shortly after core body temp nadir, which occurs 2 to 3 hours before natural wake time. Melatonin should be given 5 to 6 hours prior to dim-light melatonin onset (DLMO). DLMO is 13 to 14 hours after natural wake time.


                 2.  Advanced sleep phase disorder


                      a.  Go to sleep early, wake up early


                      b.  Linked to hPer2 gene; less common than delayed phase; occurs in middle-aged adults


                      c.  Diagnosis: sleep history and sleep log+/– actigraphy


                      d.  Treatment: early-evening light therapy (7–9 p.m.) or chronotherapy (advance bedtime by 3 hours every few days)


                 3.  Non-24-hour sleep wake disorder


                      a.  Sleep occurs later and later each day and then the cycle repeats itself.


                      b.  Mostly seen in the blind (no light to regulate cycle)


                      c.  Diagnosis: sleep history and sleep log; complaint has to be present for at least 2 months; actigraphy can be helpful.


                      d.  Treatment: melatonin (3–10 mg) 1 hour before bedtime and structured bedtime routines


                 4.  Irregular sleep–wake cycle


                      a.  Disorganized: intermittent periods of sleep and wake throughout 24-hour period


                      b.  Common in older adults with dementia


                      c.  Diagnosis: sleep history and sleep log +/– actigraphy


                      d.  Treatment: morning light exposure, structured daytime activities, and sleep-conducive nocturnal environment


                 5.  Jet lag


                      a.  Recurrent insomnia and daytime somnolence due to rapid travel across two or more time zones


                      b.  Non-sleep symptoms can include malaise, impaired daytime alertness, poor appetite, gastrointestinal (GI) disturbances, menstrual irregularities, decreased cognitive processing, depression, anxiety, and irritability


                      c.  Eastward travelers may be more at risk.


                      d.  Diagnosis: sleep history +/– sleep log


                      e.  Treatment: if the expected stay in the destination is going to be 2 days or less, adapting to the destination’s time zone is not needed. Appropriately timed light exposure is a key component: if traveling eastward, light exposure in the mornings to advance circadian clock; if traveling westward, light exposure in evening to delay circadian rhythm.


                       f.  Melatonin can be used (best if used with appropriate light exposure). If traveling east, take melatonin in the evening for 2 weeks prior to travel and then at bedtime once in destination.


                 6.  Shift-work sleep disorder


                      a.  Sleepiness during work hours and insomnia during designated sleep periods for at least 1 month


                      b.  Overnight shift most susceptible


                      c.  Can result in chronic sleep deprivation and lead to fatigue, mood disorder, GI disturbance, decreased libido; increased risk for polysubstance abuse, weight gain, hypertension, and coronary artery disease


                      d.  Diagnosis: sleep history and at least 2 weeks of sleep log


                      e.  Treatment: aimed at increasing alertness during work hours and facilitating sleep during designated sleep hours. For night-shift workers, bright light exposure up to 2 hours before end of shift can increase alertness. Minimize light exposure on commute home (sunglasses) and have dark, quiet environment to help fall asleep.


                       f.  Melatonin can be taken at time of sleep, which may help to improve daytime sleep, but does not help with work-hour alertness. Modafinil and armodafinil are treatments approved by the U.S. Food and Drug Administration (FDA) to improve work-hour performance/alertness.


           C.  Sleep-disordered breathing


                 1.  Key definitions


                      a.  Obstructive apnea: cessation of airflow with continued respiratory effort, due to complete upper airway occlusion.


                      b.  Hypopnea: significant decrease in airflow with associated EEG arousal or oxygen desaturation due to partial upper airway collapse


                      c.  Central apnea: cessation of airflow without respiratory effort


                      d.  Mixed apnea: components of central and obstructive apneas


                      e.  Upper airway resistance syndrome: flow limitation, not meeting criteria for apnea or hypopnea; due to narrowed upper airway


                       f.  Primary snoring: snoring without respiratory compromise


                 2.  Obstructive sleep apnea (OSA): 1.5 to 4 times more common in men, prevalence increases with age


                      a.  Anatomical risk factors: high arched palate, narrow airway, retrognathia, adenotonsillar hypertrophy, elongated/edematous uvula, enlarged tongue, increased neck circumference, obesity


                      b.  STOP BANG screening tool; high risk is yes to 5 or more questions


                              i.  Snoring, tired, observed apneas, pressure (elevated blood pressure), body mass index (BMI) (greater than 35), age (over 50), neck circumference (greater than 40 cm), gender (male)


                                   (A)  Snoring most common symptom


                                   (B)  Diagnosis: by PSG (apnea hypopnea index [AHI] of 5–15 with daytime symptoms or AHI greater than 16)


                                           (1)  AHI: mild = 5 to 14, moderate = 15 to 30, severe = greater than 30


                                   (C)  Treatment: conservative therapies include weight loss, sleep repositioning therapy (if OSA was more prominent during supine position sleep in nonsupine position), maintaining patency of nasal airway, and avoiding sedatives, narcotics, opioids, and alcohol (ETOH).


                                   (D)  First-line therapy is positive airway pressure (PAP) [Continuous PAP (CPAP), Bilevel PAP (BIPAP), Automatic PAP (APAP)]—pressurized air in oronasal cavity to act as a stent to maintain patency of airway.


                                   (E)  If intolerant to PAP or mild to moderate OSA, can use dental appliance (tongue retaining device or mandibular advancement device) or nasal Expiratory PAP (EPAP)


                                   (F)  If severe OSA and unable to use PAP, surgical intervention can be considered (uvulopalatopharyngoplasty most common, but variety of procedures, including septoplasty or turbinate reduction, tonsillectomy, hyoid suspension, and mandibular advancement)


                                   (G)  If patient is morbidly obese, bariatric surgery may help to improve sleep-disordered breathing.


                                   (H)  The main heath risk associated with untreated OSA is cardiovascular, including hypertension, atrial fibrillation, myocardial infarction, congestive heart failure, and stroke.


                                     (I)  OSA also linked to increased risk of metabolic syndrome and autonomic alterations


                 3.  Central sleep apnea (CSA)


                      a.  Normally, when CO2 levels rise, there is a certain point at which central sensors in the medulla are stimulated and peripheral sensors in the carotid body are activated to initiate a breath.


                      b.  Central sleep apnea can occur in association with chronic hypocapnic states (such as congestive heart failure (CHF) or high altitude) in which the body becomes accustomed to lower CO2 states and the set point to trigger a breath is reduced, leading to apneas.


                      c.  Other conditions in which CSA is common: with reduced respiratory drive (with opiates/narcotics) or in association with diaphragmatic weakness as can be seen in neuromuscular disorders such as Amyotrophic Lateral Sclerosis (ALS)


                      d.  Diagnosis: PSG with same AHI criteria as OSA


                      e.  Treatment: PAP therapy; sometimes triggered respirations are required. Acetazolamide can be used.


                       f.  Appropriate cardiopulmonary and neurologic workup


                 4.  Sleep-related hypoventilation


                      a.  Most commonly seen with obesity hypoventilation syndrome (OHS)


                      b.  OHS diagnosis: BMI greater than 30, waking PaCO2 level of 45 mmHg or greater, hypoxemia PaO2 of 70 mmHg or less


                      c.  Higher risk of pulmonary hypertension


           D.  Hypersomnia


                 1.  Narcolepsy with cataplexy


                      a.  Excessive daytime sleepiness (EDS) for at least 3 months


                      b.  Cataplexy (loss of muscle tone triggered by strong emotions)


                      c.  Diagnosis: Multiple Sleep Latency Test (MSLT) with mean sleep-onset latency (MSOL) 8 minutes or less and two or more sleep-onset REM periods (SOREMPs) or a decreased cerebrospinal fluid (CSF) hypocretin level (less than 110 pg/mL)


                 2.  Narcolepsy without cataplexy


                      a.  EDS for at least 3 months


                      b.  No cataplexy


                      c.  Diagnosis: MSLT criteria only (MSOL of 8 minutes or less and two or more SOREMPs)


                      d.  Narcolepsy key points:


                              i.  Narcolepsy with cataplexy associated with HLA-DQB1-0602 and low hypocretin levels


                             ii.  Bimodal peak at 15 years of age and near 35 years of age


                            iii.  Clinical features aside from EDS and cataplexy include sleep hallucinations, sleep paralysis, and nonconsolidated sleep.


                 3.  Idiopathic hypersomnia (IH)


                      a.  EDS for 3 months or more


                      b.  Diagnosis: MSLT with MSOL 8 minutes or less and less than two SOREMPs


                      c.  Can be further classified as IH with long sleep time (patient getting 10 or more hours of sleep per sleep period) or without long sleep time (6–10 hours of sleep)


                 4.  Kleine-Levin syndrome and menstrual-related hypersomnia


                      a.  Recurrent episodes of EDS for 2 days to 4 weeks


                      b.  Episodes occur at least yearly


                      c.  Baseline (normal) function between attacks


                      d.  Often accompanied by mood and cognitive alterations, increased appetite, aggressive or hypersexual behavior


                 5.  Treatment


                      a.  Traditional stimulants (amphetamines, methamphetamine, methylphenidate) or wake-promoting agents that act primarily on norepinephrine and dopamine (modafinil, armodafinil); sodium oxybate acting on GABA-b receptors consolidates sleep and can increase slow-wave sleep—better sleep may allow for more alertness during the day.


                      b.  Cataplexy is treated with tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs).


           E.  Parasomnias: undesirable behaviors that occur during sleep, characterized by complex, seemingly purposeful behaviors, usually longer than 2 minutes, with no conscious recollection of event


                 1.  The first distinction to make is NREM versus REM parasomnias:


                      a.  NREM parasomnias: usually arise from slow-wave sleep during the first half of the night


                              i.  Confusional arousal: mental confusion or confusional behavior that occurs from waking during nocturnal sleep or a nap; episodes usually last a few minutes; generally no recollection of the event; abnormal sexual behavior (sexsomnia) is a type of confusional arousal.


                                   (A)  Treatment: episodes starting in childhood usually spontaneously remit.


                             ii.  Sleepwalking or somnambulism: walking or more complex behaviors with eyes generally open


                                   (A)  Peak prevalence ages 8 to 12 years; usually remits spontaneously in teens/early adulthood


                            iii.  Sleep terrors or parvor nocturnus: sudden arousal, sitting up with cry/vocalization and look of fear; associated with tachycardia, tachypnea, diaphoresis, mydriasis, and facial flushing; episodes usually last a few minutes and then patient returns to normal sleep, with no recollection of event upon waking


                                   (A)  Peak prevalence is early school age, with remission usually by teens.


                      b.  REM parasomnias—occur during second half of night (when REM periods are longer)


                 2.  Nightmares: although similar to night terrors in that patient appears to have a sudden arousal with fear/panic, the patient is cognizant that he or she is waking up because of a nightmare and is often able to recall the dream with detail. Most often, there is recollection of the event in the morning.


                 3.  REM sleep behavior disorder (RBD)


                      a.  Dream reenactment behavior with motor activity and vocalization


                      b.  Usually occurring about once per week


                      c.  This is the only parasomnia that has a definitive PSG diagnosis: there is REM sleep without atonia (RSWA), which is demonstrated by persistent chin EMG activity during REM sleep.


                      d.  Can be due to bilateral pontine tegmental lesions


                      e.  Associated with alpha synucleinopathies (Parkinson’s disease, dementia with Lewy bodies), with RBD often preceding the neurodegenerative disorder


                       f.  RBD can also be secondary (induced by medications, including SSRIs, SNRIs, alcohol withdrawal, caffeine)


                      g.  Pseudo RBD: occurs with untreated OSA; subsides with appropriate treatment of OSA


                      h.  Treatment: safe sleep environment and clonazepam


           F.  Nocturnal epilepsies


                 1.  Two main types: frontal lobe and temporal lobe epilepsy


                 2.  Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE): brief, motor seizures; associated with nicotinic acetylcholine receptor gene (CHRNA4/CHRNB2 subunits)


                 3.  Frontal lobe seizures associated with clonic activity, dystonic posturing, vocalization, and tendency toward secondary generalization; awareness can be preserved; minimal post-episode confusion


                 4.  Temporal lobe seizures are usually longer episodes associated with automatisms. Awareness is usually preserved, but post-episode confusion is more common. Less likely to generalize.


           G.  Periodic limb movement disorder/restless leg syndrome (RLS)


                 1.  Periodic limb movement disorder (PLMD): PSG diagnosis with increased PLMs (significant if PLM index is greater than 15); generally no treatment unless clinical complaints (poor sleep with increased nocturnal waking, EDS) with no other explanation


                 2.  RLS


                      a.  Clinical diagnosis often associated with increased PLMs (but not a requirement)


                      b.  RLS can be secondary to other medical conditions, including iron deficiency, diabetes mellitus, renal failure, and pregnancy.


                      c.  Prevalence of RLS is 5% to 10% in general population, but 10% to 26% in pregnancy, with peak in the third trimester.


                      d.  Diagnosis of RLS (four key features)


                              i.  An urge to move legs; can be accompanied by uncomfortable and unpleasant leg sensations


                             ii.  The symptoms begin or worsen during times of rest.


                            iii.  The symptoms improve with movement.


                            iv.  The symptoms are worse during evening/night.


                      e.  Workup: check ferritin level (can be associated with low ferritin) and peripheral neuropathy labs (B12, TSH, HgbA1c).


                       f.  Treatment: if serum ferritin levels less than 50 u/L, treat with iron supplementation +/– medical workup for anemia. Other treatments include dopaminergic agents (dopamine agonists and dopamine replacement—first line), GABA agents, BZDs, and opioids (last line).


                      g.  Monitor for compulsive behaviors with dopaminergic agents.


                      h.  Augmentation (where symptoms occur earlier in the day, are more severe, or involve more body parts) can occur with dopaminergic agents; initially can increase frequency of doses, but eventually may require discontinuation of medication.


      V.  Pharmacology Overview


           A.  Medications for insomnia


                 1.  BZDs act as GABA agonists. However, because they have nonspecific GABA attachment sites, BZDs may have a more widespread brain effect (versus just sleep effects).


                 2.  FDA-approved BZDs include flurazepam and quazepam (long half-lives), temazepam and estazolam (medium half-lives), and triazolam (short half-life)


                 3.  BZDs are most commonly used for short-term treatment of insomnia.


                 4.  The most common side effects are drowsiness, dizziness, and headache.


                 5.  There is habit-forming potential.


                 6.  Use with caution in patients with untreated OSA or respiratory disease, as these medications can potentially lower respiratory drive.


                 7.  Non-BZD receptor agonists are modulators of GABA-a receptor complex.


                 8.  FDA-approved non-BZDs include eszopiclone (long half-life), zolpidem (medium half-life), and zaleplon (short half-life)


                 9.  Can be used for short-term or, if needed, longer-term treatment of insomnia


               10.  Remember that eszopiclone is associated with metallic taste and smell.


               11.  All non-BZDs have the potential to increase parasomnias (abnormal nighttime behaviors).


               12.  There are extended-release formulations as well as oral spray and sublingual forms of zolpidem.


               13.  Selective melatonin receptor agonist


                      a.  Ramelteon: used mostly for sleep-onset insomnia


               14.  Selective histamine H1 receptor antagonist


                      a.  Doxepin: long half-life, used for sleep maintenance insomnia; can have side effect of upper respiratory tract infection


           B.  Medications for hypersomnia


                 1.  Stimulants include amphetamine, methamphetamine, and methylphenidate.


                 2.  Side effects include palpitations, tachycardia, hypertension, anorexia, psychosis, insomnia, and high abuse potential.


                 3.  Wake-promoting agents


                      a.  Modafinil and armodafinil (act on dopamine receptors) to enhance wakefulness state; common side effect is headache/nausea


                 4.  Sodium oxybate


                      a.  Activates GABA-b receptors


                      b.  Consolidates sleep; increases slow-wave sleep; by providing improved sleep quality, enhances daytime alertness


           C.  Medications for cataplexy


                 1.  Tricyclic antidepressants (imipramine, protriptyline, clomipramine)


                      a.  SSRIs (fluoxetine and fluvoxamine)


                      b.  SNRI (venlafaxine)


                      c.  Sodium oxybate


           D.  Medications for RLS


                 1.  Dopamine agonists (generally first-line treatment)


                      a.  Include pramipexole, ropinirole, rotigotine patch, carbidopa/levodopa


                      b.  These medications are most often efficacious for RLS.


                      c.  Side effects include risk of augmentations (making RLS symptoms worse during the daytime), impulse control disorders, and daytime sleepiness.


                      d.  Impulse control disorders can occur in 6% to 17% of people taking dopaminergic agents and can manifest months after starting treatment.


                 2.  Calcium channel alpha 2 delta ligands (generally first- or second-line agents)


                      a.  Gabapentin, gabapentin enacarbil, pregabalin


                      b.  Especially helpful if patients also have neuropathic symptoms


                      c.  BZDs and opioids are useful as third-line agents for RLS treatment.


 

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Nov 10, 2016 | Posted by in NEUROLOGY | Comments Off on Sleep and Sleep Disorders

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