*With the exception of programs from the ACCEL series, each of which qualifies for up to 4 Category 1 CME credits.
NEW Audio-Digest Neurology
Volume 04, Issue 05
March 7, 2013
Excessive Daytime Sleepiness Karl Doghramji, MD
Insomnia Dr. Doghramji
From Sleep Medicine Symposium: What’s New Under The Moon, Presented By Jefferson Medical College Of Thomas Jefferson University And The Jefferson Sleep Disorders Center
The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.
Neurology Program Info Accreditation InfoCultural & Linguistic Competency Resources
From Sleep Medicine Symposium: What’s New Under the Moon, presented by Jefferson Medical College of Thomas Jefferson University and the Jefferson Sleep Disorders Center
Karl Doghramji, MD, Professor of Psychiatry, Neurology, and Medicine; Medical Director, Jefferson Sleep Disorders Center; and Program Director, Fellowship in Sleep Medicine, Thomas Jefferson University, Philadelphia, PA
The goal of this program is to improve the diagnosis and treatment of sleep disorders. After hearing and assimilating this program, the clinician will be better able to:
1. Treat circadian rhythm sleep disorders with chronotherapy and bright light therapy.
2. Prevent and manage shift work sleep disorder.
3. Summarize symptoms and pathophysiology of narcolepsy.
4. Advise patients on the importance of sleep hygiene and cognitive behavioral treatment for insomnia.
5. Prescribe appropriate medications for patients with wake after sleep onset disorders, secondary insomnias, and restless legs syndrome.
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Doghramji is a consultant for Elan Corporation, Jazz Pharmaceuticals, and UCB SA, and owns stock in Merck & Co. The planning committee reported nothing to disclose. In his lecture, Dr. Doghramji presents information that is related to the experimental use of a therapy, product, or device.
Excessive Daytime Sleepiness
Differential diagnosis: excessive sleepiness defined as tendency to fall asleep at inappropriate times that improves with sleep; fatigue defined as sense of weariness, lassitude, or lack of energy that improves with rest
Consequences of sleep deprivation and sleepiness: problems with mental performance — poor short-term memory or recall; errors of omission and commission; diminished insight into subtle meanings; cardiovascular morbidity and mortality — increase in blood pressure (BP), proinflammatory cytokines, obesity, and ghrelin (neuropeptide that promotes obesity); decreased leptin; immune response — reduced; legal implications — motor vehicle accidents that involve sleep-deprived driver considered criminal homicide in New Jersey
Associated diseases and conditions: chronic sleep deprivation — study found 2 days of sleep deprivation caused high rates of lapses in attention and errors on testing; individuals who sleep 4 hr per night reach same rate of errors after 2 wk; even 8 hr of sleep per night over prolonged periods produces increased rates of attention lapse
Modulators: adenosine controls degree of sleepiness and wakefulness; as individual remains awake during day, sleep debt accumulates and maximizes at 11:00 pm (possibly because of buildup of adenosine)
Circadian rhythm: area in suprachiasmatic nucleus controls internal clock; during day, signals sent to antagonize adenosine; body temperature and levels of plasma cortisol and melatonin synchronized with time of day and sleep-wake rhythm
Circadian rhythm sleep disorders: result from desynchronization between intrinsic circadian clock, sleep-wake cycle, and external time of day; irregular sleep-wake cycle — patient naps throughout day (often occurs in elderly or blind); some patients have non-24-hr rhythm; delayed sleep phase syndrome (DSPS) — onset of sleep delayed 2 to 3 hr; prevalence 7% to 16% in young people; syndrome generally outgrown; cause unknown; advanced sleep phase syndrome (ASPS) — prevalence ≈1% in middle-aged men; caused by mutation in circadian gene; allele predicts inability to adapt sleep patterns (eg, for shift work) or withstand sleep deprivation; diagnosis — actigraphy; subjective sleep-wake logs available
Treatment of DSPS: chronotherapy — delay sleep and wake times by 2 to 3 hr each day; phase advance therapy — use bright artificial light (2000 to 10,000 lux) in morning; wear darkening goggles for 1 to 2 hr at night; take melatonin in evening (1 mg, 4 hr before bedtime); advance rhythm by 15 min/day
Treatment of ASPS: use light in evening; speaker does not advocate use of melatonin in morning; gradually delay sleep and wake times
Side effects of bright light therapy: headache, visual disturbances, and nausea; ultraviolet or infrared light may damage eye; not indicated in patients with retinopathies and glaucoma; light can interact with photosensitizing drugs
Shift work disorder: sleep and wake cycle shifted, but endogenous rhythms desynchronized; increases likelihood of mood disorders, depression, ulcers, cardiometabolic dysfunction, stroke, and cancer; studies show insulin resistance increases in individuals who do shift work
Prevention and management: sleep ≥8 hr/day; work ≤12 hr/day; avoid unpredictable or rotating shifts; night shifts with weekend variation less harmful; constant shifts best; healthy sleep habits — use ear plugs; darken bedroom; minimize interruptions; perform regular exercise; avoid alcohol and caffeine within 10 hr of bedtime; avoid exercise near bedtime; planned nap — 20 min helpful; sleep inertia may cause mistakes on waking; avoid driving if drowsy; caffeine — ≈0.33 cup of coffee per hour helpful (increases alertness and performance); if overly done can cause intoxication (psychologic and physical symptoms), tolerance, and difficulty withdrawing; timed light exposure — 10,000 lux helps workers adapt to shift work; melatonin — speaker recommends 0.5 to 1 mg at ≈1 hr before bedtime in morning; armodafinil and modafinil — approved for shift work disorder; help patients remain awake at night; Drug Enforcement Administration (DEA) Schedule IV with side effects including headache, nausea, and dizziness; rare potential for rash (Stevens-Johnson syndrome; discontinue medication and do not rechallenge); interactions with cytochrome P450 3A4 enzyme system may diminish effectiveness of oral contraceptives
Narcolepsy: possibly more common than generally thought; prevalence estimated at ≈0.2%; symptoms — excessive daytime sleepiness (EDS) primary; cataplexy characterized by sudden weakness of muscles triggered by emotions; hypnagogic hallucinations and sleep paralysis; fragmented sleep (especially rapid eye movement [REM] sleep); diagnosis — often delayed; peak incidence occurs at 15 to 20 yr of age, diagnosis usually made at 30 to 35 yr of age; often unrecognized in school; pathophysiology — caused by dysfunction in small group of cells in perifornical area of hypothalamus that harbors hypocretins (orexins), ie, neuropeptides that impinge on neurotransmitters in norepinephrine, epinephrine, serotonin, and other systems; hypocretins thought to control transition between wake and sleep; narcoleptic patients lack hypocretins because cells destroyed, possibly by autoimmune process controlled by HLA-DR2 antigen; criteria for diagnosis — mean sleep latency of <8 min on multiple sleep latency test, ≥2 sleep-onset REM episodes, and normal sleep study on previous night; some laboratories evaluate concentration of hypocretins in cerebral spinal fluid (CSF)
Treatment: medications include amphetamines, methylphenidate derivatives, modafinil and armodafinil, and sodium oxybate; strategy involves use of long-acting medication (eg, armodafinil, modafinil) mixed with short-acting amphetamine or methylphenidate on as-needed basis; side effects include dry mouth, dyspepsia, and headache; possible to avoid side effects by slowly increasing dosage; cataplexy — drugs include ϒ-hydroxy butyrate, sodium oxybate (Xyrem), and some antidepressants (eg, protriptyline, clomipramine) that strongly suppress REM sleep; sodium oxybate — taken twice per night in liquid form to normalize sleep and prevent daytime sleepiness; DEA Schedule III (requires central pharmacy; none of other agents restricted); side effects include headache, nausea, dizziness, somnolence, enuresis, and nocturnal sedation
Evaluation of EDS: Epworth Sleepiness Scale useful for diagnosis and tracking effects of medication
Risk factors: increasing age; female sex (risk increased 2-fold); divorce or separation; unemployment; shift work; darker periods of year; psychiatric syndromes; smoking; consumption of alcohol and coffee; drugs and medications
Classification: primary — associated with many impairments, eg, high systolic and diastolic BP; involves hyperarousal in central nervous system (CNS) and throughout body (eg, cardiovascular system, sympathetic activation, heightened metabolic activity in brain, cognitive arousal); these cause elevated sympathetic discharge which increase BP, blood sugar, rates of mortality, and psychomotor deficit
Treatment: for secondary comorbid insomnia, treat comorbidities first, eg, antidepressants for major depression or treat reflux in cases of gastroesophageal reflux disease (GERD); for primary insomnia, use sleep hygiene education as first approach
Sleep hygiene: wake up at same time every morning (resets circadian rhythm for next 24 hr); increase exposure to bright light in morning and maximize darkness before bedtime (eg, wear sunglasses); exercise regularly; set aside time to worry; establish comfortable sleep environment; do something relaxing before bed; avoid — alcohol; caffeine between 10 to 12 hr before bedtime; exposure to bright light at night; exercise within 3 to 4 hr of bedtime; heavy meals or drinking before bedtime; napping; watching clock
Cognitive behavioral treatments: stimulus control therapy — get out of bed if unable to fall asleep within 20 min and return to bed when sleepy; relaxation therapies — biofeedback; relaxation training; cognitive behavioral therapy (CBT) — combines approaches; extremely helpful
Medications for wake after sleep onset: doxepin (3 mg) at bedtime or zolpidem (sublingual) immediately after waking; zaleplon (Sonata) and zolpidem (eg, Ambien, Edluar, Intermezzo) decrease sleep latency but do not address wake after sleep onset; zolpidem extended release and eszopiclone (Lunesta) address wake after sleep onset; ramelteon (Rozerem) decreases sleep latency but not effective for wake after sleep; doxepin (low dose, eg, 3 mg, 6 mg) indicated for wake after sleep onset; recently introduced variants of zolpidem — sublingual form (Edluar) and oral spray form have more rapid onset of action but not indicated for wake after sleep onset; sublingual form useful if patient has ≥4 hr of time to sleep remaining; speaker asks patient to decide whether to use an agent before bed or after waking at night
Side effects: benzodiazepine receptor agonists — daytime sedation and rebound insomnia; DEA schedule IV (potential for abuse); melatonin receptor agonist (ramelteon) — has no potential for abuse (useful for patients with history of drug abuse); histamine H1 receptor antagonist (doxepin) — no potential for abuse; sleep amnesia — patients may drive or walk while asleep; uncertain whether effect limited to zolpidem; possibly more frequent when used with other sedative medications or alcohol and at higher doses; natural compounds — no data support use of melatonin, L-tryptophan, or other natural agents for insomnia; efficacy and safety unknown
Strategy for discontinuation: begin CBT and taper use of sleeping pills; study evaluated CBT alone, tapering of medication, or CBT combined with tapering in older adults on prolonged treatment with benzodiazepines; found optimal results with combination; begin CBT at onset of treatment for optimal results; study comparing CBT and pharmacotherapy for insomnia in older adults showed CBT alone produced best results over 2 yr
Case example: 32-yr-old man had difficulty falling asleep and multiple awakenings; tension in legs, arms, and abdomen (mainly while sitting) and electrical feeling deep in legs; symptoms worsened at night; partially relieved by walking; patient had generalized anxiety disorder, irritable bowel syndrome, and diabetes; took fluoxetine (eg, Prozac, Rapiflux, Sarafem); probable diagnoses include restless legs syndrome (RLS) and akathisia (motor restlessness induced by psychotropic agents)
Differential diagnosis of RLS: urge to move legs primary symptom; usually begins in evening but can occur during day; partially relieved by movement, eg, rubbing; worse in evening or night; periodic limb movement (PLM) disorder — produces bursts of muscle activity (jerks) during sleep; generally asymptomatic; peripheral neuropathy — mainly involves pain (eg, sensory phenomenon) that worsens with activity; peripheral vascular disease — also shows worsening of pain with activity; cramps — involve specific muscle groups; neuroleptic-induced akathisia — occurs with many antipsychotics and antidepressants; anxiety — usually involves entire body throughout day; ≈80% of patients with RLS also have PLM, but most patients with PLM do not report RLS
Clinical features of RLS: prevalence increases with age; more common in women; primary form — unrelated to underlying pathophysiology; more common in young individuals; often associated with positive family history; secondary form — more common in elderly; positive family history less likely; often caused by iron deficiency, end-stage renal disease, pregnancy (occurs in 25% of pregnant women and resolves after delivery), Parkinson disease, and pharmacotherapy; cause — unknown; possibly related to deficiency in dopaminergic system of CNS; dopa acts as precursor in synthesis of dopamine (important in motor control); rate-limiting step catalyzed by tyrosine hydroxylase, which converts tyrosine to dopa; enzyme dependent on levels of iron, which acts as cofactor
Evaluation and treatment of RLS: test for serum ferritin; sleep study and complete blood count (CBC) not necessary (RLS symptomatic diagnosis); if serum ferritin <50 ng/mL, supplementation with iron improves symptoms in 20% to 30% of patients even if CBC results normal; supplement with ferrous sulfate (FeSO4) plus vitamin C to increase absorption; dopaminergic agents indicated for treatment of RLS — include pramipexole (Mirapex), ropinirole (Repreve, Requip), and rotigotine patch (Neupro; with 24-hr activity); oral agents shorter acting; side effects include morning rebound and augmentation in which RLS symptoms occur in morning or earlier than previously; speaker increases dose for augmentation and provides continuous coverage for rebound (agents can cause daytime sleepiness); gabapentin enacarbil — only nondopaminergic agent indicated for RLS; different salt than gabapentin (eg, Gralise, Horizant, Neurontin); taken at dinner time (600 mg); blood levels stable over 24 hr; use with caution in patients with poor renal function; side effects include somnolence and dizziness but no rebound or augmentation
Case example: 72-yr-old man with difficulty sleeping; probably had depression as suggested by anhedonia, although he denied feeling depressed; ≈40% of patients with insomnia have comorbid psychiatric disorder, eg, anxiety disorder, major depression, dysthymia, substance abuse; long-lasting insomnia increases chance of developing depression; after treatment with escitalopram (Lexapro), symptoms of depression improved but insomnia continued; speaker recommends increasing dose of antidepressant; common mistakes in treating patients with insomnia and underlying depression include inadequate dose, duration, and use of psychiatric consultations; if insomnia associated with GERD, treatment with proton pump inhibitor improves sleep (treatment with sleeping pill increases exposure to acid and risk for adenocarcinoma of esophagus)
Consider referral to sleep expert: patients with possible obstructive sleep apnea, PLM, narcolepsy, violent behaviors in sleep, dangerous daytime sleepiness; patients whose insomnia fails to respond to treatment
Dr. Doghramji spoke at Sleep Medicine Symposium: What’s New Under the Moon, held November 2, 2012, in Philadelphia, PA, and presented by Jefferson Medical College of Thomas Jefferson University and the Jefferson Sleep Disorders Center. To learn more about CME meetings presented by the Jefferson Medical College of Thomas Jefferson University, please visit jeffline.jefferson.edu/jeffcme. The Audio-Digest Foundation thanks Dr. Doghramji and Jefferson Medical College of Thomas Jefferson University for their cooperation in the production of this program.
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