PHYSIOLOGY OF SLEEP

Sleep is a process necessary for life and is considered essential for restoration of energy, consolidation of memory and learning, and maintenance of the immune system. From a physiologic perspective, sleep can be divided into four stages: rapid eye movement (REM) sleep and three stages of nonrapid eye movement (nREM) sleep. REM sleep is distinguished not only by rapid eye movements, as its name indicates, but also by atonia of all skeletal muscles other than the extraocular muscles and diaphragm. The three stages of nREM sleep are distinguished from each other by electroencephalogram (EEG) features. Stage N1 is a transitional state between wakefulness and sleep and is characterized electrophysiologically by attenuation of the posterior dominant background rhythm on EEG. Stage N2 is intermediate sleep and features sleep spindles and K complexes. Stage N3 is also known as deep or slow wave sleep and is characterized by an EEG background that consists of more than 20% of the record in the delta frequency (0.5–2 Hz) range.

A typical night of sleep contains four to six cycles lasting approximately 90 minutes each, with an orderly progression between stages as shown in Figure 13-1. Note that stage N1 sleep is absent after the first sleep cycle and that both N3 and REM sleep follow stage N2. Infants spend approximately 50% of sleep in REM, with this percentage decreasing to the typical young adult value of 20% to 25% between ages 2 and 5 years. Healthy older adults have a decrease in REM sleep to 15% to 20% of the night. As illustrated in Figure 13-1, REM sleep accounts for a greater percentage of sleep as the night progresses.

Certain drugs and toxins may alter the proportion of the night spent in the various stages of sleep. For example, benzodiazepines suppress stage N3, whereas antidepressants and alcohol suppress REM sleep.

POLYSOMNOGRAPHY

Apart from the history and physical examination, polysomnography (PSG) is the most important step in the evaluation of a patient with a suspected sleep disorder. The PSG consists of a limited EEG montage, which records brain activity and helps with the staging of sleep, electro-oculography to monitor eye movements, surface electromyography electrodes attached to the chin and legs to monitor skeletal muscle activity, transducers to measure airflow and chest movements, pulse oximetry to measure oxygen saturation, and electrocardiogram to monitor cardiac activity. Standard PSG may be augmented by video monitoring to investigate for parasomnias such as REM sleep behavior disorder and somnambulism.

FIGURE 13-1. Stages of sleep. Rapid eye movement (REM) sleep and the three stages of non-REM sleep alternate throughout the night in cycles that last approximately 90 minutes. There are typically four to six cycles each night in a healthy young adult.

CIRCADIAN RHYTHMS AND SLEEP-PHASE DISORDERS

The body is governed by roughly 24-hour cycles of sleep and activity known as circadian rhythms. These rhythms are coordinated by the suprachiasmatic nucleus of the hypothalamus, with important inputs from melatonin produced by the pineal gland. Pathologic circadian rhythms include advanced sleep-phase disorder in which patients sleep or awaken earlier than they desire and delayed sleep-phase disorder in which sleep onset is delayed until early morning, with consequent awakening later than desired. Diagnosis of a circadian rhythm disorder is made by keeping a sleep log. Bright light therapy and melatonin can treat sleep-phase disorders by resetting circadian rhythms.

RESTLESS LEGS SYNDROME/PERIODIC LIMB MOVEMENTS OF SLEEP

Restless legs syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs, usually during periods of rest or inactivity. Patients describe uncomfortable crawling sensations in the legs, with worsening discomfort if the legs remain still, and relief when they are moved. Typically, restless legs symptoms occur in the evening or at night. They are often accompanied by periodic limb movements of sleep, which are repetitive involuntary movements of the toe, ankle, knee, and hip that last 2 to 3 seconds and are followed by slow recovery of the normal leg position. These movements can awaken the patient, but generally are more bothersome to the bed partner. RLS is more common in women, and in some families an autosomal dominant inheritance pattern is probable.

Diagnosis of RLS is made by clinical history. PSG may help to confirm the diagnosis but is often not necessary. Laboratory evaluation of RLS should include measurement of ferritin levels, as many patients with RLS have iron deficiency.

The dopamine agonists ropinirole and pramipexole are often the preferred initial treatments for RLS. Typically, they are administered 2 to 3 hours prior to symptom onset in the evening. Many patients require an afternoon dose. Side effects of dopamine agonists include nausea, lightheadedness, and sometimes sleep attacks (falling asleep suddenly in the daytime). The most important side effect of dopamine agonists for RLS patients, however, is augmentation in which symptoms develop progressively earlier in the day. If augmentation becomes a severe problem or RLS symptoms worsen despite treatment with dopaminergic agents, other options include gabapentin, pregabalin (which may be less likely to produce augmentation than dopaminergic agents), levodopa, opioids, and benzodiazepines. Rotigotine is a transdermal dopamine agonist, which may produce less augmentation. Correction of iron deficiency can help to relieve symptoms, although dopaminergic agents are often required even after this is accomplished.

NARCOLEPSY/CATAPLEXY

The four components of the narcolepsy/cataplexy syndrome are excessive daytime sleepiness with narcolepsy, cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy is the irresistible urge to sleep, often taking the form of sleep attacks, that is, falling asleep suddenly in the daytime. Cataplexy is characterized by the sudden loss of muscle tone, often in the setting of laughter or other strong emotions, and is the most specific feature of the syndrome. Hypnagogic hallucinations are those that occur immediately upon falling asleep.

Onset of narcolepsy/cataplexy syndrome usually occurs in the late teens or twenties. The pathophysiology of narcolepsy/cataplexy is related to loss of hypocretin-secreting neurons in the hypothalamus. A cerebrospinal fluid hypocretin level <110 pg/mL is diagnostic for the syndrome in the appropriate clinical setting. More typically, however, the diagnosis is established by performing a special type of PSG known as the multiple sleep latency test (MSLT). An MSLT involves several short naps and monitoring of the latency to sleep onset and latency to REM onset. Sleep latency of less than 8 minutes, with more than two episodes of REM at sleep onset, is diagnostic for narcolepsy/cataplexy.

Modafinil, an alerting agent with an unclear mechanism of action, is typically the first agent employed for patients with narcolepsy. Amphetamines such as methylphenidate and dextroamphetamine are also employed, but less frequently due to safety concerns and potential for abuse. Cataplexy is most often treated with the gamma-aminobutyric acid metabolite sodium oxybate. Tricyclic antidepressants such as clomipramine and selective serotonin reuptake inhibitors including fluoxetine and venlafaxine are also options for treating cataplexy.

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