1. Define and characterize the types, patterns, and stages of sleep.

2. Evaluate sleep deprivation using subjective and objective measures.

3. Diagnose and treat restless legs syndrome, periodic limb movement disorder, and narcolepsy.

4. Recognize the causes of insomnia and choose among behavioral and pharmacologic treatment options.

5. Describe the relationships between sleep and cancer.

Overview of Sleep Disorders and Sleep Deprivation
Richard J. Schwab, MD, Associate Professor, Department of Medicine, Division of Sleep Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center, Philadelphia

Background: types of sleep—rapid eye movement (REM) sleep; non-REM sleep; stages of sleep—stage 2 characterized by spindles and K complexes; delta (stage 3 or 4) sleep characterized by wide QRS-like complexes and slower electroencephalography (EEG)

Consensus statement (recommendations from experts; not field-tested): use frontal leads to detect slow-wave sleep; combine stages 3 and 4 sleep; voltage criteria changed for scoring periodic limb movements (PLMs); EMG activity changed for bruxism; changes in REM behavior disorder (RBD); use thermal sensor to detect apneas and nasal pressure to detect hypopneas; change in scoring based on percentage reduction in excursion

Sleep patterns: delta sleep decreases with age; teenagers need more sleep; REM episodes increase in length and number as night progresses; ideal sleep consists of 20% to 25% REM; amount of sleep obtained by Americans declined by 20% over last century to 7 hr on average, with 80% of adolescents getting suboptimal amount; sleep deprivation— causes reduced productivity, lower cognitive performance, decreased quality of life (QOL), and accidents

Vehicular accidents: National Sleep Foundation reports 37% of drivers have fallen asleep while driving (higher rate for teenagers); truck drivers get only 5 hr of sleep on average, and 15% to 20% have undiagnosed sleep apnea; level of impairment from 24 hr of sleep deprivation equivalent to being intoxicated; more severe accidents result from drivers who fall asleep; legal considerations—jail penalties imposed for fatal accidents caused by drivers who fall asleep in New Jersey and England

Measuring sleep deprivation: Epworth Sleepiness Scale (ESS)—questionnaire with normal score <10 (fast and easy to use, but results variable); multiple sleep latency test (MSLT) and maintenance of wakefulness test—MSLT used for narcolepsy and central nervous system hypersomnolence; measures time to onset of sleep during series of 20-min naps; normal result >8 to 10 min; <5 min defined as sleepy; 2 REM onsets suggests narcolepsy

Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): RLS—patients have difficulty falling asleep and unusual sensations in legs that improve with movement; sensations can involve arm or neck; PLMD—limb movements occur during sleep; often overlaps with RLS; polysomnography (PSG) criteria for PLMD—movements last 0.5 to 5 sec; occur at defined intervals; decrease during REM and delta sleep; treat PLMD only if symptomatic

Conditions associated with RLS/PLMD: iron deficiency anemia (ferritin levels <50 µg/L); if RLS worsens suddenly, consider evaluating for gastrointestinal (GI) bleeding; also seen in patients with uremia, neuropathy, pregnancy, and certain medications

Treatment of choice: ropinirole (Requip) pramipexole (Mirapex); pergolide (Permax) discontinued because of risk for valvular heart disease; carbidopa plus levodopa (eg, Sinemet) can cause augmentation (ie, symptoms appear earlier in day)

Second-line agents: iron therapy, clonazepam (Klonopin), opiates, or gabapentin (eg, Neurontin)

Narcolepsy: diagnosis often delayed 11 yr; diagnostic pentad—extreme sleepiness; cataplexy lasting 2 to 10 min with consciousness maintained; vivid dreams at onset of sleep or upon awakening; sleep paralysis that remains after awakening; increased number of arousals; PSG shows REM onset <90 min and fragmented sleep; MSLT shows 2 REM onsets with short latency to stage 1 sleep

Treatment: daytime naps; modafinil (Provigil) for wakefulness; γ-hydroxybutyrate (sodium oxybate; Xyrem) for cataplexy; modafinil—indicated for narcolepsy, sleep apnea if patient complies with continuous positive airway pressure (CPAP), and shift work; data emerging on use for depression, multiple sclerosis, and attention deficit disorder; γ- hydroxybutyrate—indicated for cataplexy and daytime sleepiness; potential for misuse (date rape)

REM behavior disorder: older men may act out dreams and strike sleep partners; treat with clonazepam; possibly linked to Parkinson’s disease

Sleepwalking: usually occurs in children or adolescents during slow-wave sleep; episodes last <10 min; family history often present; patients confused on awakening and do not remember events; high risk for injury (education required); typically occurs when person sleep-deprived; can be induced by alcohol

Insomnia: causes—sleep apnea, RLS/PLMD; circadian rhythm disorders; caffeine 8 to 12 hr before sleep; some pulmonary medications; chronic medical conditions (eg, neurologic conditions, lung disease); psychophysiologic insomnia

Treatment: cognitive behavioral therapy (CBT) effective but underutilized; hypnotics—alcohol not effective (causes sleep disruption); diphenhydramine (eg, Benadryl) should not be used because of long half-life and anticholinergic effects; newer medications do not disturb sleep architecture; ramelteon (Rozerem) acts as melatonin agonist and can be used long-term; eszopiclone (Lunesta) effective but causes metallic taste; ramelteon must be used for several weeks but not always effective

Insomnia: Outcomes and Multidisciplinary Treatment
David N. Neubauer, MD, Assistant Professor of Psychiatry, Johns Hopkins University School of Medicine; Associate Director, Johns Hopkins Sleep Disorders Center, Baltimore, MD

Diagnostic criteria: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and International Classification of Sleep Disorders (ICSD)-2 define insomnia as lasting >1 mo; symptoms include difficulty falling or staying asleep, awakening too early, and poor quality of sleep; daytime consequences must exist

Epidemiology: 30% of general population have occasional insomnia; ≈10% have persistent or severe symptoms and daytime functional impairment; 50% of patients receiving treatment for other chronic disorders have insomnia

Causes: predisposing factors include personality issues and lifestyle; precipitants include situational disturbances, psychologic conditioning (eg, hyperarousal), poor sleep habits, caffeine, psychiatric, medical, and sleep disorders, and medications; often multifactorial

Types: primary (independent of other disorders) and secondary or comorbid (presumed association with other disorders)

Common comorbidities: congestive heart failure; rheumatologic disorders (eg, fibromyalgia); psychiatric and mood disorders (especially recurrent major depression, bipolar disorder, anxiety disorders); substance abuse; sleep disorders, including circadian rhythm disorders (eg, delayed or advanced sleep phase patterns), sleep-disordered breathing, and RLS

Medical outcome study sponsored by National Institutes of Health (NIH): highlights importance of insomnia in patients with chronic medical conditions

National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Study: surveyed 8000 individuals; 40% of those who had insomnia for 2 wk had anxiety disorders, mood disorders (eg, major depression, dysthymia), substance abuse, or other psychiatric disorders

Models of primary insomnia: psychophysiologic (conditioned arousal); underlying predisposition for insomnia proposed; studies of individuals with primary insomnia show greater EEG activation before sleep onset and in early part of sleep, abnormalities in secretion of cortisol and cytokines, and in thermoregulation; also, neuroimaging studies

Outcomes: include effects on QOL; lower productivity; large societal burden from increased health care costs; studies show future health risks and increased risk for falls

Daytime complaints: fatigue; poor concentration and memory; irritability; problems with relationships

Future health risks: medical—recent studies show individuals with insomnia at greater risk of developing medical problems (eg, new-onset hypertension, mortality from coronary artery disease, diabetes mellitus); sleep restriction study demonstrated abnormal glucose tolerance when participants limited to 4 hr of sleep for 6 nights; psychiatric—NIH study showed increased risk for new-onset mood and anxiety disorders and substance abuse; insomnia also independently predicts future suicide

Evaluation: include in routine history and review-of-systems forms; sleep logs and diaries (charts or graphs) helpful

Treatment: education key; sleep hygiene—includes regular sleep cycle, exercise, appropriate exposure to light and dark; enhancement of sleep environment (slightly cool room ideal); avoid heavy meals at bedtime and caffeine, alcohol, and nicotine; study showed that, in smokers, alpha activity (arousal) increased and delta activity (deep sleep) decreased at night; behavioral strategies—cognitive therapy; relaxation training; restriction of nonsleep time in bed; stimulus control

CBT: study comparing CBT, placebo, and relaxation therapy showed CBT significantly improved total sleep time and wake after sleep onset (WASO) time; meta-analysis of 59 studies found improvement in sleep onset latency, WASO, and total sleep time

Substances: recent improvements include innovations in pharmacodynamics and pharmacokinetics; United States Food and Drug Administration (FDA) now has fewer restrictions on duration of use and differentiates drugs that address sleep onset from those that affect sleep maintenance; Drug Enforcement Administration (DEA) has changed scheduling for hypnotics

Benzodiazepine receptor agonists (BZRAs): work through γ-aminobutyric acid (GABA); targeted action at ventrolateral preoptic nucleus (VLPO); BZRAs bind to site on GABAA receptor complex, allowing increased hyperpolarization; act as positive allosteric modulators; newer nonbenzodiazepines have similar activity; all cause rapid onset of sleep; half-lives of older medications ranged from 2 hr to 2 days; newer ones range from 1 to 7 hr

Dosing: take at bedtime; allow sufficient time in bed; reduce dose for older patients; useful nightly or as needed; consider tapering dose to discontinue

Adverse effects: mostly well tolerated; some somnambulism and confused behaviors observed

Selective melatonin receptor agonist: enhances sleepiness caused by increasing melatonin levels at bedtime; ramelteon acts as selective agonist for receptor subtypes MT1 and MT2 , and works through suprachiasmatic nucleus in anterior hypothalamus; no abuse liability and not DEA-controlled

Adverse effects: somnolence, dizziness, and fatigue

Dosing: take 30 min before bedtime; avoid hazardous activities; not for patients with severe hepatic impairment or those taking fluvoxamine

Recently approved medications: eszopiclone and zolpidem extended release (ER) beneficial for sleep maintenance

Duration of use: eszopiclone, ramelteon and zolpidem ER not limited to short-term use

Sleep and Cancer
Richard D. Simon Jr, MD, Clinical Assistant Professor of Medicine, University of Washington School of Medicine, Seattle; Medical Director, Kathryn Severyns Dement Sleep Disorders Center, Walla Walla, WA

Background: 33% of patients with cancer have insomnia; 50% have fatigue; many have RLS; nearly 30% complain of sleepiness; hypnotics most frequently prescribed psychotropic medications for patients with cancer; often, patients with cancer experience dampening of circadian amplitude and slight phase advance; study of 102 terminally ill patients found poor sleep quality significantly associated with desire for withdrawal of care and death

Delayed sleep phase syndrome (DSPS): patients cannot fall asleep or awaken at desired time; patients with breast cancer and DSPS have more fatigue; treatment—morning light and minimization of evening light; melatonin in evening; apply basic circadian principles; bright light during day significantly improves functional performance

Systemic management of pain: opiates cause altered mental status, respiratory depression, and worsening of obstructive sleep apnea (OSA); patients should wear CPAP during day if likely to sleep; have patient on medications during titration for CPAP

Other medications: include anti-anxiety agents (eg, benzodiazepines), anti-nausea agents, and antidepressants; evaluate whether patient achieves desired outcome and consider discontinuing medication if not

Sleep disorders in patients with cancer: OSA—increased by radiation to head and neck; RLS and PLMS—very common because of low ferritin levels and use of antihistamines and antidepressants; 88% of women with breast cancer have insomnia (intervention suggested)

Cancer physiology: may disrupt circadian rhythm and homeostatic sleep drive; circulating tumor necrosis factor (TNF), interleukins, interferons, and immune modulators cause fatigue and affect sleep; link between sleep and immune system

Fatigue management: ask about snoring, and if present, test for OSA and manage with CPAP; ask about RLS and treat; educate patients about sleep hygiene principles; for insomnia, consider all treatment options, including CBT; control pain adequately, but be aware of fatigue as consequence of drug therapy; bright light during desired awake time; stimulant medications and corticosteroids help with daytime fatigue

Effects on cancer treatment: study showed patients with metastatic colon cancer who had good 24-hr sleep-wake cycle survived longer; circadian timing for chemotherapy—studies in mice and humans showed better survival and fewer adverse effects when chronotherapy used, eg, in patients with breast cancer, administering 5-fluorouracil at 4:00 AM; chronotherapy also may decrease mucosal toxicity and peripheral neuropathy and increase QOL

Cancer causing sleep disorders: 0.24% of patients with OSA have head and neck tumor as cause; any tumor or irradiation in hypothalamic area may cause daytime sleepiness or insomnia

Biological clock (BC): clock/BMAL1 proteins form dimmers and cause transcription of other clock gene proteins; coordinated by suprachiasmatic nucleus; cycle found in all cells; synthesis of clock gene proteins stimulated and accumulate during daylight and metabolized at night; DNA repair mechanisms—also regulated by BC and clock gene proteins; abnormalities in checkpoint pathway cause genetic instability, mutagenesis, and increased risk for progression of cancer; mutations in BC alter response to agents that damage DNA; BC defects or altered expression patterns found in colorectal, breast, endometrial, and pancreatic cancers; coordinating DNA synthesis and S-phase checkpoint with day/night cycle may minimize replication stress

Abnormal BC genes and cancer: period genes dysregulated in acute myelogenous leukemia (AML), and abnormal in 95% of breast cancers; also, dysregulation found in endometrial and pancreatic cancer cells

Circadian rhythms and cancer: known human tumor suppressors may be involved in circadian core mechanism; evidence includes inhibition by melatonin of tumorigenesis in mice and humans; risk for breast cancer significantly increased in shift workers, and risk for endometrial cancer greater in obese shift workers