Neurologic Aspects of Sleep Medicine




Keywords

sleep, neurology, sleep physiology, polysomnography, circadian neurobiology, neuroanatomy of sleep, obstructive sleep apnea, narcolepsy, circadian rhythm disorders, insomnia, restless legs syndrome, parasomnias, Alzheimer disease, Parkinson disease, headache, stroke, epilepsy

 


Sleep disorders commonly occur in patients who present to neurologists. At times, symptoms are obvious, such as insomnia or excessive daytime sleepiness. However, some patients have serious sleep disorders, such as sleep apnea, that are often not readily apparent to the patient or physician and can exacerbate a neurologic disorder. Established links exist between sleep apnea and stroke, epilepsy, and migraine, between certain sleep behavior disorders and neurodegenerative diseases, and between circadian rhythm disorders and dementia. In light of these links, it is important that neurologists become familiar with sleep disorders and incorporate sleep diagnosis and treatment into daily practice, and that sleep specialists and internists gain wider appreciation of the impact of sleep disorders on neurologic function and disease. This chapter reviews key aspects of sleep medicine and their association with clinical neurology.




Sleep Physiology


Sleep is defined by behavioral and physiologic changes that include postural recumbence, behavioral quiescence, eye closure, and specific physiologic parameters based on electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG). Sleep is further subdivided into non–rapid eye movement (NREM) and rapid eye movement (REM) sleep.


The normal adult brain enters sleep first through NREM stages followed by REM sleep approximately 90 minutes later. NREM and REM sleep then alternate through four to six cycles lasting 90 to 110 minutes each. The first third of sleep is dominated by NREM sleep and the last third of the night is dominated by REM sleep. NREM sleep is further divided into three stages (N1, N2, N3).


Sleep Stages


The staging of sleep is based on the recordings of the EEG, chin EMG and EOG made during polysomnography (PSG). The PSG is scored by assigning a sleep stage to each 30-second epoch recorded. The characteristics of the various sleep stages are summarized in Figure 51-1 .




Figure 51-1


The stages of sleep. A , Stage N1. There is low-voltage mixed-frequency electrocerebral activity with ongoing muscle activity and slow, rolling eye movements. B , Stage N2 sleep showing sleep spindles. K-complexes are also classically present but are not clearly shown in this epoch. C , Stage N3 sleep, with high-amplitude, low-frequency delta activity in the electroencephalogram (EEG). The eye-movement channels reflect the EEG. D , Stage REM. The EEG is of low amplitude and mixed frequency and is accompanied by muscle atonia and rapid eye movements.

(Adapted from Abad VC, Guilleminault C: Polysomnographic evaluation of sleep disorders. p. 727. In Aminoff MJ (ed): Aminoff’s Electrodiagnosis in Clinical Neurology. 6th Ed. Elsevier Saunders, Oxford, 2012.)


Stage Wake


Stage wake can occur when the subject is alert with eyes open or relaxed with eyes closed. When the eyes are open, the EEG shows low-amplitude, fast mixed-frequency activity. The EOG tracing consists of eye movements and eye blinks, and the EMG chin activity is increased. Once the eyes are closed, alpha rhythms (8 to 13 Hz) predominate on the EEG and are most prominent in the occipital leads. This alpha activity attenuates with concentration or with eye opening. Stage W is scored when 50 percent of the epoch shows alpha activity in the occipital region. The normal adult spends less than 5 percent of the night in this stage.


Stage N1


Stage N1 sleep is characterized by light sleep or drowsiness. It is identified by less than 50 percent of the epoch being occupied by alpha activity on the EEG. The EEG also shows low-voltage, mixed-frequency activity predominantly in the theta frequency (4 to 7 Hz). The EOG channel often shows slow rolling eye movements, and EMG activity is diminished. Vertex sharp waves may appear in the central EEG leads in the later part of stage N1. In the normal adult, stage N1 should occupy 2 to 5 percent of sleep, but patients with excessive sleep fragmentation such as those with sleep apnea often have a larger percentage of stage N1 sleep.


Stage N2


Stage N2 sleep is defined by the presence of K-complexes or sleep spindles on the EEG. The background EEG shows low-amplitude, mixed-frequency activity. The EOG typically shows no eye movements, but slow rolling eye movements may persist from stage N1. EMG activity is reduced from stage N1 and wake. Stage N2 generally constitutes 45 to 55 percent of sleep in adults.


Stage N3


Stage N3 sleep, also referred to as slow-wave sleep, represents the deepest sleep stage. Slow-wave sleep was initially divided into stages 3 and 4; however, because of the physiologic similarities between these stages, they have been combined into a single stage. Stage N3 is defined by the presence of high-amplitude slow waves with a frequency of 0.5 to 2 Hz and an amplitude of 75 µV. Slow-wave activity must occupy at least 20 percent of the epoch to meet criteria for stage N3. The EMG is active but diminished compared to stages W and N1, and there are no eye movements. Stage N3 occupies 15 to 25 percent of sleep in healthy adults.


Stage REM


REM sleep is characterized by a highly active brain with loss of muscle tone. The EEG shows a low-voltage, mixed-frequency pattern with sawtooth waves. The chin EMG tone is markedly diminished, and the EOG shows rapid eye movements. There is a cessation of K complexes, sleep spindles, and high-amplitude waves. REM sleep accounts for 20 to 25 percent of total sleep time in healthy adults.


Sleep Patterns Across the Human Lifespan


Sleep patterns change markedly throughout the human lifespan. The most pronounced changes occur during the first year of life. Newborns enter sleep through REM sleep (called “active sleep” in the newborn), and then sleep alternates between REM and NREM in 50- to 60-minute intervals rather than the 90-minute cycles of adults. During the first year of life, EEG patterns develop to allow distinction between different stages of NREM sleep.


Stage N3 sleep is most prominent in childhood and decreases by almost 40 percent in the second decade of life. It further declines with age and is almost absent by the age of 60, especially in men, perhaps due to a decline in the amplitude of EEG waves from reduced synaptic activity.


REM sleep occupies 50 percent of sleep in the first year of life. By 6 years of age, REM sleep time is reduced to 20 to 25 percent of sleep and is maintained at this percentage into old age. REM sleep markedly declines with organic brain dysfunction.


Arousals and episodes of awakening from sleep increase dramatically with age and may correlate with an underlying sleep disorder, medical condition, or neurologic disease. The percentage of stage N1 sleep also increases with age, signifying more transitions between wake and sleep.


Sleep requirements change with age. A newborn sleeps about 16 hours per day. This falls to about 11 hours in children 3 to 5 years of age. Adolescents between 9 and 10 years of age require approximately 10 hours of sleep. Adults average 7.5 to 8 hours of sleep; although this duration remains steady into healthy old age, the ability to consolidate sleep into one a single continuous sleep period declines. Elderly individuals may revert to a biphasic sleep pattern with increased daytime napping.




Circadian Neurobiology


The sleep-wake cycle is regulated by two opposing processes, the circadian rhythm and the homeostatic drive for sleep. The circadian rhythm is set by the suprachiasmatic nucleus of the hypothalamus, which regulates the sleep-wake cycle. The suprachiasmatic nucleus projects to the pineal gland to release melatonin, which promotes sleep. The nucleus is synchronized by external cues known as zeitgebers , of which the strongest is light. Light inhibits the release of melatonin from the pineal gland and in this way sleep is influenced by the day-night cycle.


The homeostatic process refers to an increased propensity for sleepiness with longer periods of being awake. Adenosine is a byproduct of the waking brain, and levels rise with prolonged periods of wake, increasing the tendency for sleep. Caffeine is an adenosine antagonist and is used to promote wakefulness.


In the morning, the suprachiasmatic nucleus output is low. The homeostatic drive increases over the day and is opposed by increased output from the suprachiasmatic nucleus. By the end of the day, suprachiasmatic nucleus output is decreased through inhibition by melatonin, and the homeostatic drive is increased, resulting in the onset of sleep.


The circadian rhythm of sleep becomes clinically relevant when the sleep-wake cycle is changed such as in shift work or jet lag. Adaptation becomes difficult both because of sleep loss and increased homeostatic drive for sleep and because the circadian rhythm continues on its own established schedule. Elderly individuals who have difficulty consolidating sleep and those with neurodegenerative diseases often have disruption of the normal cycling of sleep consistent with circadian rhythm disorders. Light therapy can be a useful tool to help reset the circadian rhythm and establish a normal sleep-wake cycle.




Neuroanatomy of Sleep


Changes between wake, NREM, and REM sleep are produced through modulation of neurotransmitters and neuromodulaters interconnecting the neuronal system that regulates sleep.


The ascending arousal system is important in maintaining wakefulness. It is composed of a cholinergic branch and a monoaminergic branch. The cholinergic branch includes the pedunculopontine and laterodorsal tegmental nuclei, which project to the thalamic reticular nucleus in order to activate the cerebral cortex. Acetylcholine excites the thalamic and cortical neurons maximally during wake and REM sleep.


The monoaminergic branch includes the locus coeruleus, dorsal and median raphe nuclei, tuberomammilary nuclei, and ventral periaqueductal gray matter. Histamine, norepinephrine, and serotonin are released from these various nuclei, which are also maximally active during wakefulness in order to activate the cerebral cortex. The monoaminergic system is quiet in NREM sleep and turned off in REM sleep. Hypocretin neurons in the lateral hypothalamus augment this activation of the cortex during wakefulness.


Dopamine is elevated during periods of wakefulness, and dopaminergic neurons modulate cortical activation indirectly through regulatory activity of the globus pallidus and the thalamus.


Sleep onset is associated with a rapid deactivation of both the monoaminergic and cholinergic branches of the arousal system. GABAergic neurons in the preoptic hypothalamus promote sleep onset. The ventrolateral preoptic nucleus sends descending inhibitory projections to multiple arousal systems during sleep.


The homeostatic process and the circadian clock determine the activity of the ventrolateral preoptic nucleus. In NREM sleep, this nucleus inhibits both the cholinergic and monoaminergic branches of the ascending arousal system to induce sleep. In REM sleep, only the monoaminergic nuclei are inhibited, but the cholinergic nuclei are active.


REM sleep is driven by cholinergic neurons in the pons. Descending cholinergic projections produce muscle atonia by activating neurons in the pontine reticular formation and ventral reticular formation that then project to the spinal cord. Glycine is the essential neurotransmitter in these pathways.


The monoaminergic nuclei also inhibit the ascending arousal system during wakefulness, resulting in a system of reciprocal inhibition. This has been termed the “sleep switch.” Both sides of the switch strongly inhibit each other, resulting in a feedback loop with only two possible states: sleep and wakefulness.


Hypocretin is the stabilizer of this switch. In wakefulness, hypocretin reinforces the arousal system to avert unwanted switches into sleep. Narcolepsy with cataplexy is a disorder of low levels of hypocretin, causing a lack of stability in the “sleep switch,” resulting in frequent and unwanted transitions between sleep and wakefulness.




Approach to the Patient with Sleep Disorders


Clinical Evaluation


Complaints related to sleep and wakefulness are pervasive in the general population. Approximately 30 percent of adults report one or more symptoms of insomnia including difficulty falling asleep, staying asleep, awakening too early, or nonrestorative sleep. It is estimated that 4 to 21 percent experience excessive daytime sleepiness at least 3 days per week. Only 6 percent of patients with sleep complaints see a physician specifically for a sleep problem, and many others resort to over-the-counter medications or self-remedies.


Sleep disorders are associated with significant morbidity and mortality. Insomnia, for example, is associated with impairment of all aspects of quality of life including physical functioning, bodily pain, social functioning, and mental health. Obstructive sleep apnea increases the risk of cardiovascular and cerebrovascular disease as well as causing motor vehicle accidents.


Individuals with sleep disturbances present with any of four main complaints. The first is insomnia, which may be described as difficulty in falling asleep or staying asleep, having an insufficient amount of sleep, or poor quality of sleep. The second is excessive daytime sleepiness (EDS), which may manifest as feelings of lack of energy or tiredness associated with naps, falling asleep at inappropriate times, or difficulty with concentration or memory. The most common cause of EDS is insufficient time for sleep. The third complaint is of abnormal sleep behavior, usually described by a bed partner. The fourth is of an inability to sleep at the desired time. A single sleep disorder may be associated with multiple complaints.


It is important to understand the motivation of patients in seeking treatment. For example, insomnia may impact job performance and cause a concern for loss of employment. A complaint of snoring may present only after a person is forced to sleep in a separate room to prevent disturbing a bed partner. The International Classification of Sleep Disorders (ICSD) has helped unify the approach to sleep complaints by classifying over 80 sleep disorders.


Patients should fill out a sleep questionnaire and a 1- to 2-week sleep diary. The questionnaire should address the patients’ usual sleep hours, nocturnal awakenings, daytime napping, work hours, snoring, daytime functioning, sleep environment, movements in sleep (e.g., leg movements), abnormal behaviors in sleep (e.g., sleepwalking), lifestyle factors (e.g., caffeine intake), weight changes, past medical history, social history, medications, family history of sleep disorders, and other sleep symptoms (e.g., cataplexy or sleep paralysis). A sleep diary should record the time of getting in and out of bed, sleep onset time, awakenings, naps, exercise, sleep medication, and caffeine intake. There are several scales used to assess the degree of daytime sleepiness in a person, such as the Epworth Sleepiness Scale, that can help with diagnosis.


In addition to general medical and neurologic examinations, the physical examination should include the patients’ weight, height, body mass index, blood pressure, and neck circumference. The upper airway should be inspected for pharyngeal narrowing, tonsillar enlargement, uvula enlargement or edema, a large tongue, low-lying palate, and micrognathia, all of which are risk factors for sleep apnea.


Laboratory Testing


Polysomnography


The PSG is the most useful diagnostic tool in sleep medicine. Several physiologic variables are recorded during the PSG, including EEG, EMG of the chin and legs, EOG, electrocardiogram, airflow through the nose and mouth, respiratory effort, and oxygen saturation.


The EEG is usually performed using six channels: two frontal leads, two central leads, and two occipital leads. Various stages of sleep are better identified using particular leads, such as identifying delta waves primarily in the frontal leads. A full EEG montage is sometimes used to differentiate parasomnias from epileptiform activity. The EMG of the chin is important in identifying the reduction in muscle tone seen during REM sleep. The EMG of both legs helps capture periodic limb movements in sleep. The EOG is used to identify characteristic eye movements, such as occur during REM sleep. A thermistor or nasal cannula records airflow by monitoring temperature changes. The nasal cannula is attached to a pressure transducer and is more accurate in detecting respiratory changes such as hypopneas. Respiratory effort is recorded using piezoelectric belts around the chest and abdomen in order to differentiate obstructive from central apneas, which are characterized by a complete lack of respiratory effort. A pulse oximeter is usually worn on the finger to monitor oxygen saturation.


The PSG should also include videography to record behavioral changes in sleep, a body position monitor, and snore recording. Sleep is recorded in 30-second intervals termed epochs.


PSG is useful for the diagnosis of sleep-related breathing disorders, narcolepsy, periodic limb movement disorder, and REM sleep behavior disorder. When a patient is diagnosed with sleep apnea, the PSG is also used to determine the optimal positive airway pressure (PAP) for treatment; titration can be performed on two separate nights or, alternatively, a split-night study can be performed. During the split-night study, the patient is observed for the first 2 to 3 hours for signs of sleep apnea and, if it is detected, the technician will interrupt the study and begin titration. Certain sleep disorders do not require PSG, such as insomnia, restless legs syndrome, and circadian rhythm disorders, unless a concomitant breathing disorder is suspected.


Multiple Sleep Latency Test


The multiple sleep latency test (MSLT) is used to document pathologic daytime sleepiness and to make a diagnosis of narcolepsy or idiopathic hypersomnia. It consists of five nap opportunities each 2 hours apart beginning 2 hours after the termination of the nocturnal PSG. The recording montage consists of the EEG, chin EMG, EOG, and electrocardiogram. Each nap is terminated either 20 minutes after starting (if the patient does not fall asleep) or 15 minutes after the first 30-second epoch of sleep.


The average latency to sleep onset across all five naps is calculated. A mean sleep latency of 8 minutes or less with at least two sleep-onset REM periods strongly suggests a diagnosis of narcolepsy. It is important that the MSLT is performed after at least 6 hours of total sleep time because sleep deprivation can mimic narcolepsy.


Maintenance of Wakefulness Test


The maintenance of wakefulness test, a variation of the MSLT, measures a person’s ability to stay awake in the daytime. It is useful in determining the effects of treatment on daytime sleepiness and consists of four trials of remaining awake while sedentary every 2 hours, beginning 2 hours after the patient has awakened from nighttime sleep. Each trial is terminated after 40 minutes if the patient remains awake or after the first three consecutive epochs of stage N1 sleep or the first epoch of any other stage of sleep. The mean sleep latency across all four naps is calculated. This test is often used to assess the ability of commercial drivers to remain awake at work.


Actigraphy


Actigraphy is used to objectively assess the patient’s sleep-wake schedule in the normal environment for a 1- to 2-week period. The actigraph is worn on the nondominant wrist and detects small movements to establish periods of rest and activity which equate with wake and sleep. It is most useful in patients with circadian rhythm disorders or insomnia.


Home Sleep Studies


A home sleep study is a simplified version of a PSG that usually focuses exclusively on respiratory parameters, without measurement of sleep stages. There are various versions, but all should include nasal airflow, respiratory effort, and an oximeter. According to guidelines, home sleep studies should only be used in patients with a high pretest probability of having obstructive sleep apnea. In practice, it is used in patients with suspected severe uncomplicated obstructive sleep apnea to confirm the diagnosis. The home sleep study is not clinically useful for patients with suspected insomnia, narcolepsy, circadian rhythm disorders, parasomnias, or nocturnal movement disorders.




Insomnia


Standardized Definitions


Insomnia is one of the most prevalent health complaints, with 30 to 50 percent of the population reporting transient insomnia. When even more specific diagnostic criteria are utilized, the rates still range between 5 percent and 20 percent.


Criteria for insomnia differ somewhat between the three main classification systems: International Classification of Diseases, 10th edition (ICD); Diagnostic and Statistical Manual, Treatment Revision, 4th edition (DSM-IV-TR); and International Classification of Sleep Disorders, 2nd edition (ICSD-2). The ICSD-2 describes 11 subtypes of insomnia that all have as a hallmark symptom a sleep disturbance defined as difficulty initiating sleep, difficulty maintaining sleep, early morning awakenings, or sleep that is of poor quality or nonrestorative. The DSM-IV requires a prominent complaint similar to the ICSD-2, but has a time cut-off, requiring symptoms to be present for at least 1 month. The ICD-10 requires that sleep disturbance must occur at least 3 nights per week.


For many years, insomnia was thought of as a symptom of another underlying condition. Classification symptoms all distinguish between forms of “primary” (insomnia occurring without any comorbidities) and “secondary” insomnia (insomnia due to another disorder). Clinical practice has traditionally been to treat the “cause” first, with the belief that insomnia would remit after the underlying condition was addressed. A major shift in this line of thought has taken place in recent years, with a significant amount of research negating the view of primary and secondary insomnia. The relationship between sleep and psychiatric disorders appears to be bidirectional, and causative factors can be extremely difficult to separate from the insomnia itself. The symptom of “nonrestorative” sleep has also been called into question as it is typically related to another sleep disorder that impairs sleep quality.


Risk Factors and Common Comorbidities


Insomnia is most commonly seen in women, older adults, populations with lower socioeconomic status, those with divorce or marital separation, and in those with comorbid psychiatric or medical disorders. Insomnia is commonly observed in neurologic disorders, particularly Parkinson disease, Alzheimer disease, epilepsy, stroke, multiple sclerosis, and traumatic brain injury. Patients with medical conditions such as pain disorders and heart disease are all at increased risk of insomnia.


Consequences


Insomnia is a risk factor for the development of anxiety, depression, substance use, and suicidality. It is also associated with poor attention and concentration, increased work absenteeism, higher medical costs, increased rates of motor vehicle accidents, more falls in the elderly, and reduced overall quality of life.


Clinical Assessment and Diagnosis


The history should focus on symptoms, chronology, exacerbating and alleviating factors, social, medical, and psychiatric precipitants and comorbidities, as well as previous therapies and their success. Symptoms of insomnia range from difficulty in falling or staying asleep to early morning awakenings, or a combination of these symptoms.


Understanding a patient’s typical sleep-wake periods (on weekdays and weekends) and what the patient does both during the day (including work schedule, napping, and exercise) and in the hours leading up to bedtime and throughout the night is important. A detailed analysis of the patient’s thoughts and attitudes about sleep and maladaptive behavioral strategies is crucial to design effective treatment. Symptoms of any other sleep disorders that might impact sleep quality should be assessed, such as snoring, restless legs, apnea, pain, and parasomnias. A medication (prescription and over-the-counter) and substance use history (including time of day taken) is important and should include any caffeine, alcohol, or tobacco use. Table 51-1 lists medications and substances commonly associated with insomnia and Table 51-2 summarizes common comorbid medical conditions.



Table 51-1

Medications and Substances Commonly Associated With Insomnia























Alcohol
Caffeine
Nicotine
Antidepressants
Decongestants
Corticosteroids
Bronchodilators
β-Adrenergic antagonists
Stimulants
Statins


Table 51-2

Medical Conditions Commonly Comorbid with Insomnia

















Neurologic: stroke, Parkinson disease, neuropathy, traumatic brain injury
Pulmonary: chronic obstructive pulmonary disease, asthma
Endocrine: diabetes, hypertension
Renal: chronic renal failure
Rheumatologic: rheumatoid arthritis, fibromyalgia, osteoarthritis
Cardiovascular: congestive heart failure, coronary artery disease
Gastrointestinal: gastroesophageal reflux


The most common assessment tools for insomnia include a sleep diary and questionnaires such as the Insomnia Severity Index and the Pittsburgh Sleep Quality Index. Overnight PSG may be warranted in cases in which a comorbid additional sleep disorder is considered or when treatment for insomnia has been unsuccessful. Actigraphy can be useful for establishing circadian disturbances that may be contributory as well as for tracking sleep-wake times and treatment response.


Pathophysiology


Insomnia is considered a disorder of hyperarousal, with patients demonstrating higher levels of cortisol, increased basal metabolic rates, and the presence of excessive beta or gamma activity on EEG.


The 3P model describes the development and maintenance of chronic insomnia. This model suggests that individuals may be vulnerable to developing insomnia based on predisposing factors that may be biologic (e.g., a diagnosis of chronic pain), psychologic (e.g., a family history of anxiety), or social (e.g., working shifts). Precipitating factors (e.g., a divorce or cancer diagnosis) may start an acute insomnia episode that is followed by behaviors that perpetuate a chronic insomnia, including worrying about sleep or consequences of poor sleep, spending more time in bed in an attempt to catch up on sleep, napping, and using more caffeine, alcohol, or over-the-counter medications.


Treatment


Treatment for insomnia generally involves nonpharmacologic and pharmacologic approaches. Unless a main, obvious underlying cause is found, treatment should focus on insomnia as a separate diagnosis to any other medical or psychiatric issues that may present simultaneously. Nonpharmacologic treatment is always preferred as a first-line intervention, though for many patients a combination of both behavioral and pharmacologic methods may be most beneficial.


Cognitive Behavioral Therapy


Cognitive behavioral therapy (CBT) is regarded as a highly effective first-line treatment for insomnia. CBT is as effective as the newer benzodiazepine receptor agonists and appears to be more effective in the long term than pharmacologic methods. CBT is as effective in patients with or without comorbid pain, cancer, depression, and anxiety. It improves sleep onset latency, sleep quality, number of awakenings, and total sleep time. It has also been used to help taper off hypnotics; CBT and pharmacotherapy may be started together acutely and then CBT alone may be used chronically following initial gains.


CBT treatments can vary from as few as two 30- to 60-minute sessions to as many as 12 sessions. The core treatment interventions include stimulus control, sleep restriction and sleep hygiene, relaxation training, light therapy, and cognitive therapy.


Stimulus control instructs the patient to use the bed only for sleep and sex, therefore allowing the bed to become conditioned only for those two behaviors. Patients are told to go to bed only when sleepy and to get out of bed if unable to sleep and only return to bed when sleepy again. When out of bed, patients should engage in behaviors that are calm, quiet, and relaxing—all done in dim light without any screen time (e.g., television, cell phones, computers).


Sleep restriction is aimed at minimizing the gap between the amount of time the patient spends in bed and the actual amount of time they are asleep. Patients are advised to select the same awakening time daily (using an alarm) and to allow for a sleep window that approximates the average total sleep time over the past week, but never limiting this to less than 4.5 hours. Sleep hygiene aims to eliminate sleep-incompatible behaviors as described in Table 51-3 .



Table 51-3

Common Sleep Hygiene Recommendations







  • 1.

    Keep the same bedtime and wake time every day.


  • 2.

    Limit liquids, heavy meals, tobacco, and alcohol within 3 hours of bedtime.


  • 3.

    Limit caffeine at least 8 hours before bedtime.


  • 4.

    Exercise regularly, but not within 3 hours of bedtime.


  • 5.

    Wind down for at least 1 hour before bed in dim lights. Engage in something quiet, calm, and relaxing.


  • 6.

    Keep the bedroom quiet, cool, and dark.


  • 7.

    Take a hot shower or bath 1.5 to 2 hours before bedtime, not right before bed.


  • 8.

    Limit any screen time (TV, tablets, phone, computer) within an hour of bedtime and during the nighttime hours.



Cognitive therapy teaches patients to challenge maladaptive thoughts and beliefs about sleep, including minimizing worry regarding sleep time and its consequences, and to think realistically about their concerns. Relaxation therapy is helpful for some patients and may include deep breathing or muscle relaxation. Though not routinely used as a part of CBT, strategic use of bright light in the morning or before bedtime may help with some patients who may have a circadian component to their insomnia.


Pharmacologic Interventions


Benzodiazepine Receptor Agonists .


The US Food and Drug Administration (FDA) approved medications for insomnia ( Table 51-4 ) include the benzodiazepines (e.g., temazepam, flurazepam, estazolam, quazepam, triazolam) and nonbenzodiazepine hypnotics (e.g., zaleplon, zolpidem, and eszopiclone). All of the benzodiazepine receptor agonists have been shown to be efficacious and reduce sleep latency with an increase in overall sleep time. There is no single medication that is preferable to any other FDA-approved medication; the pros and cons of each (half-life, cost, past response to treatment) need to be considered with each patient.



Table 51-4

Medications Commonly Used for Treatment of Insomnia








































































FDA-Approved Pharmacologic Treatments
Drug Dose (mg) Half-Life (hrs) Insomnia Type
Zolpidem 5–10 1.5–2.4 Sleep onset/maintenance
Zolpidem CR 6.25–12.5 1.6–4.5 Sleep onset/maintenance
Zolpidem tartrate 1.75–3.5 1.4–3.6 Sleep maintenance
Eszopiclone 1–3 6 Sleep onset/maintenance
Zaleplon 5–20 1 Sleep onset
Ramelteon 8 1–2.6 Sleep onset
Doxepin 3–6 10–30 Sleep onset
Temazepam 7.5–30 8–15 Sleep maintenance
Estazolam 1–2 10–24 Sleep maintenance
Flurazepam 15–30 48–120 Sleep maintenance
Quazepam 7.5–15 39–73 Sleep maintenance
Triazolam 0.125–0.25 2–6 Sleep onset



































Common Off-Label Pharmacologic Treatments
Drug Half-Life (hrs) Side Effects
Amitriptyline 12–24 Dry mouth, dizziness, weight gain
Trazodone 3–14 Dizziness, daytime sedation, constipation
Mirtazipine 13–40 Weight gain, constipation
Quetiapine 6 Elevated liver enzymes, agitation
Olanzapine 20–54 Weight gain, orthostasis
Gabapentin 5–7 Dizziness, ataxia, nausea


These medications are all absorbed rapidly but vary in their half-life. Medications with a longer half-life may be more beneficial for a patient with sleep maintenance and early morning awakening insomnia, whereas a shorter half-life may be preferred for a patient with prolonged sleep-onset latency. Long-acting medications also have a greater risk of daytime somnolence and impaired cognitive functioning, especially in older adults. Newer medications such as zaleplon, zolpidem, and eszopiclone have fewer daytime side effects.


Longer-term efficacy and safety trials with newer nonbenzodiazepines in patients with insomnia have shown continued efficacy with increasing total sleep time and decreasing sleep latency, with overall improvement in daytime functioning and no development of physiologic tolerance. Zaleplon has a short half-life (1 hour) and is best for sleep-onset problems. Zolpidem can increase total sleep time, but the extended-release form also reduces wake time following sleep onset. A newer form of zolpidem (zolpidem tartrate) is fast-acting and aimed at middle of the night awakenings when the patient has at least 4 hours remaining before awakening; taken sublingually, it rapidly dissolves and helps the patient return to sleep. Dosages of this formulation differ based on gender (1.75 mg for women, 3.5 mg for men). Eszopiclone has been found to be effective for both sleep onset and maintenance issues.


Common side effects of benzodiazepines include residual sedation, impaired psychomotor performance, falls, and an increased risk of motor vehicle accidents. Tolerance, abuse, and dependence (especially with benzodiazepines), rebound insomnia, and anterograde amnesia are also concerns. Since these medications can reduce ventilatory drive, caution should also be used in patients with chronic obstructive pulmonary disease or untreated sleep-related breathing disorders.


The newer nonbenzodiazepines do not tend to have physiologic dependence as a concern, though psychologic dependence can develop. These medications most commonly have drowsiness, dizziness, and headaches as reported side effects. Though less commonly reported, amnesia and complex sleep-related behaviors such as sleepwalking or sleep eating have been reported.


Melatonin Receptor Agonists


Ramelteon is the only FDA-approved nonbenzodiazepine receptor agonist medication to treat sleep-onset insomnia. It is not a scheduled substance and does not act on the GABA receptors. Rather, it is a selective melatonin agonist that binds to the melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus. Particularly helpful in older adult populations, ramelteon has been shown to help increase total sleep time and reduce sleep latency. Potential side effects include drowsiness, fatigue, nausea, dizziness, and headache. It has also been studied in patients with mild-to-moderate obstructive sleep apnea, with no increase in apneic episodes.


Antidepressant Medications


Low-dose doxepin (3 to 6 mg) has recently been FDA approved as a treatment for sleep-maintenance insomnia. It is particularly useful for increasing total sleep time and sleep efficiency in patients with primary insomnia. Given their sedating properties, other antidepressants are commonly used (in much lower dosages than for depression treatment). Although limited evidence exists demonstrating efficacy in the treatment of insomnia, practitioners commonly prescribe trazodone, mirtazapine, and amitriptyline because they are perceived as safer than benzodiazepines with a lower potential for dependence. Many patients also have coexisting depression, anxiety, or both, and prescribing physicians feel that these medications may help with both mood and sleep disturbance. Side effects include drowsiness, weight gain, increased suicidal ideation in young adults, dizziness, cardiac arrhythmias, and priapism (with trazodone in particular).


Alternative Medications


Although many patients resort to over-the-counter medications as sleep aids (particularly those that contain diphenhydramine), these medications are not advised in the treatment of chronic insomnia. Atypical antipsychotics (especially quetiapine and olanzapine) are often used off-label to treat both primary insomnia and insomnia comorbid with psychiatric conditions. Case studies have reported effectiveness, particularly with older adults. However, there is a black-box warning regarding the use of antipsychotics in the elderly due to an increased risk of death. Other side effects commonly include weight gain, orthostasis, daytime sedation, agitation, and elevated liver enzymes.


Antiepileptic medications, particularly gabapentin, have also been used to treat insomnia particularly in patients with comorbid conditions (especially with generalized anxiety disorder, epilepsy, and chronic pain). Side effects include daytime sedation, dizziness, mood changes, and cognitive impairment.


The effects of melatonin taken before bedtime have not been routinely demonstrated, although some reports have suggested decreases in sleep onset latency. Generally well-tolerated by patients, melatonin is not regulated by the FDA and over-the-counter preparations can vary greatly. It is not considered a standard treatment for insomnia and appears to be better suited for treatment of circadian rhythm disorders.




Hypersomnias


EDS has many implications, including an increased risk of injury at work or home, impaired alertness, increased risk of motor vehicle accidents, and lower overall productivity. EDS can also cause psychologic stress with family, friends, and coworkers.


Narcolepsy


Narcolepsy is a disorder of EDS that is usually associated with cataplexy and other REM phenomena such as sleep paralysis and hypnagogic hallucinations. Sleep regulation and wakefulness are disrupted with rapid transitions between wakefulness and REM sleep, thereby resulting in fragmented sleep and EDS.


Although onset can occur at any age, narcolepsy most commonly begins in the second decade of life with a second peak seen around 35 years of age. There is a prolonged latency of about 10 years from the time of symptom onset to diagnosis, although improved awareness is shortening this interval. Narcolepsy is usually a sporadic disease with only 1 to 4 percent of cases being autosomal-dominantly inherited.


Clinical Features


Excessive Daytime Sleepiness


EDS is the hallmark symptom seen in all patients with narcolepsy and is characterized by a constant baseline sleepiness along with lapses into sleep throughout the day. Short naps are refreshing, but sleepiness returns within a few hours. Sleep attacks (sudden onset of sleep or the irresistible urge to sleep) can occur throughout the day. Activities that are passive increase the likelihood that sleep will occur, but in severe cases sleep attacks can occur during activities such as talking, standing, eating, or driving. Automatic behaviors (activities where the patient is functionally capable but without recall of the events) are also seen in some patients. For example, a patient can drive to a location without remembering the process of getting there.


Cataplexy


Cataplexy is defined as a sudden loss of muscle tone associated with emotion. It is pathognomonic for narcolepsy, although some patients with narcolepsy do not have cataplexy. Patients often describe knee buckling, head dropping, facial twitching, jaw dropping, or weakness of the arms. Emotions that elicit cataplexy are usually positive, such as laughter, excitement, or joy; they can also be negative, such as anger or frustration. If all striated muscles are involved, patients may fall. However, several seconds of build-up often precede a full attack, so most patients are able to sit down to prevent a fall. Patients may avoid emotional situations, such as social events where cataplexy may occur, affecting quality of life.


Sleep Paralysis


Sleep paralysis is a temporary state of involuntary immobility occurring in transitions between REM sleep and wakefulness. Patients are unable to make gross body movements or speak, but they can open their eyes and are aware of their surroundings. Episodes may last a few minutes and abate either spontaneously or when interrupted by noise or other external stimuli. Sleep paralysis can be frightening, especially when first experienced. Often sleep paralysis is accompanied by hypnagogic hallucinations. About 20 to 50 percent of patients with narcolepsy experience sleep paralysis, but sleep paralysis is also common in the general population.


Hypnagogic Hallucinations


Hypnagogic hallucinations are vivid visual, auditory, tactile, or even kinetic perceptions that, like sleep paralysis, occur during the transitions between wakefulness and REM sleep. Examples include a sensation of impending threat, feelings of suffocation, and sensations of floating, spinning, or falling. Hypnagogic hallucinations occur in 40 to 80 percent of patients with narcolepsy and cataplexy. They are easy to distinguish from the hallucinations occurring in psychiatric disease because patients with narcolepsy usually recognize the events as not real. Psychiatric hallucinations also occur at any time of day, whereas hypnagogic hallucinations surround the sleep period.


Disturbed Nocturnal Sleep


Because narcolepsy is a disorder of EDS, disturbed nocturnal sleep is often overlooked. Patients with narcolepsy typically fall asleep quickly, but have difficulty in maintaining sleep. Frequent arousals are often reported along with difficulty in falling back to sleep. The total amount of sleep in a 24-hour period is the same as in normal individuals; however, it is distributed throughout the day and night, causing daytime sleep attacks and fragmented nocturnal sleep.


Associated Symptoms


Disturbances in memory, concentration, and attention are common in narcolepsy, probably secondary to EDS. REM sleep behavior disorder and periodic limb movements may occur as well. Patients with narcolepsy also report more depressive ideation.


Patients with narcolepsy with cataplexy often have a high body mass index or obesity, attributed to metabolic changes resulting from hypocretin loss. A high body mass index may also predispose patients to developing obstructive sleep apnea; at least 25 percent of patients with narcolepsy have both conditions, which together can worsen EDS, mood, and cognition.


Diagnosis


The differential diagnosis of EDS is shown in Table 51-5 . The diagnosis of narcolepsy with cataplexy can be made based on a clear history of EDS and cataplexy. The diagnosis should be confirmed by nocturnal PSG followed by an MSLT. The diagnosis of narcolepsy without cataplexy can be more difficult and requires a PSG and MSLT.



Table 51-5

Differential Diagnosis of Excessive Daytime Sleepiness























Sleep apnea
Behaviorally induced insufficient sleep time
Idiopathic hypersomnia
Recurrent hypersomnia (Kleine–Levin syndrome)
Circadian rhythm disorder, shift work disorder
Metabolic encephalopathy
Drug intoxication or withdrawal
Depression
Epilepsy
Malingering


Nocturnal PSG shows a shortened REM latency in 50 percent of patients. Sleep efficiency is often reduced, with multiple awakenings and an increased percentage of stage N1 sleep. The MSLT should show a mean sleep latency of 8 minutes or less along with two or more sleep-onset REM periods in the setting of sufficient nocturnal sleep.


A less commonly used, but very specific and sensitive method to make the diagnosis is through measurement of cerebrospinal fluid (CSF) hypocretin-1 level, which has been shown to be less than 110 pg/ml in 90 percent of patients with narcolepsy with cataplexy. Hypocretin loss is now recognized to be the cause of human narcolepsy with cataplexy, and symptoms begin when the majority of hypocretin cells have degenerated.


Pharmacologic Treatments


There is no cure for narcolepsy. Treatment goals are to improve quality of life, EDS, and cataplexy as well as other bothersome REM phenomena. A variety of medications can be used to treat these symptoms ( Table 51-6 ).



Table 51-6

Medications Typically Prescribed for Narcolepsy












































Drug Name Dose Clinical Use Side Effects
Modafinil (Provigil) 200–400 mg daily in divided dose EDS Headache, nausea
Armodafinil (Nuvigil) 150–250 mg daily EDS Same as modafinil
Sodium oxybate (Xyrem) 4.5–9 g daily in divided doses Cataplexy, EDS, broken nighttime sleep Nausea, vomiting, dizziness
Dextroamphetamine (Dexedrine) 15–60 mg daily EDS Irritability, sweating, headaches, tremors
Methylphenidate (Ritalin) 20–60 mg daily in divided doses EDS Same as dextroamphetamine
Paroxetine (Paxil) 10–60 mg daily Cataplexy Sedation, insomnia, irritability
Phenylzine (Nardil) 15–60 mg daily in divided doses Cataplexy Impotence, weight gain, hypertension

EDS, excessive daytime sleepiness.


Excessive Daytime Sleepiness


Modafinil, armodafinil, and sodium oxybate are often used to treat EDS. The various forms of modafinil are effective wake-promoting agents with good safety and tolerability measures and a low abuse potential. Women of childbearing age taking oral contraceptives should use alternative contraception when taking modafinil or armodafinil, as the metabolism of ethinylestradiol may be increased. In the past, amphetamines were the main treatment for excessive daytime sleepiness; dextroamphetamine, methamphetamine, and combinations of amphetamine salts are helpful with improving daytime alertness, but side effects limit their use.


Cataplexy


Sodium oxybate is effective in reducing cataplexy as well as EDS. It also reduces other REM phenomena such as sleep paralysis and hypnagogic hallucinations. Due to its sedative properties, it is commonly given in divided doses at sleep onset and then 2 to 4 hours later. Common side effects include nausea, vomiting, dizziness, and nocturnal enuresis. If used as recommended, sodium oxybate is safe and has a low risk of dependence or tolerance.


Tricyclic antidepressants were initially the treatment of choice for cataplexy. Medications such as protrityline and clomipramine are effective, but side effects can be limiting. Newer norepinephrine reuptake inhibitors, such as venlafaxine and atomoxetine, may be more effective and have a more favorable side-effect profile. Selective serotonin reuptake inhibitors (SSRIs) and monoamine-oxidase inhibitors can also be used for cataplexy but are generally less effective.


Disturbed Nocturnal Sleep


Sodium oxybate increases slow-wave sleep and allows patients to sleep more continuously through the night. Newer nonbenzodiazepines such as zolpidem have also been used to consolidate nighttime sleep, but few studies have tested this approach.


Nonpharmacologic Treatments


Scheduling naps, shifting work periods to times of alertness, avoiding sugar, calculated caffeine use, and following basic sleep hygiene can all benefit patients with narcolepsy. The patient should be advised against driving, bathing, swimming, and using any heavy machinery or household appliances during times of sleepiness. Psychotherapeutic strategies for the management of stressful situations, depression, and anxiety are recommended.


Idiopathic Hypersomnia


Idiopathic hypersomnia is generally less common than narcolepsy, with symptoms beginning in teenagers or young adults. It is typically under-recognized and often a diagnosis made by excluding other causes of EDS.


The primary symptom of idiopathic hypersomnia is EDS despite a full night of sleep and normal sleep architecture; idiopathic hypersomnia includes forms with and without a long sleep time. Patients with long sleep times have at least 10 hours of sleep at night, rarely awaken during nocturnal sleep, have significant difficulty in getting up in the morning, and, unlike patients with narcolepsy, do not find naps to be refreshing. Patients usually report “sleep drunkenness”—difficulty in achieving full alertness upon awakening after a full night of sleep. Patients without long sleep times have less than 10 hours of sleep at night and are less likely to report sleep drunkenness with their EDS. The differential diagnosis of idiopathic hypersomnia is similar to that of narcolepsy.


Nocturnal PSG is routinely performed to exclude other causes of daytime sleepiness and to determine the length of sleep time. An MSLT is also performed, demonstrating EDS with a mean sleep latency of less than 8 minutes and fewer than two sleep onset REM periods (to rule out possible narcolepsy).


Treatment of idiopathic hypersomnia is similar to that of EDS in patients with narcolepsy, focusing on stimulants and wake-promoting agents, especially modafinil and armodafinil. Positive pharmacologic responses are difficult to achieve. Sleep hygiene, proper diet, and strategic use of caffeine should be utilized. Planned naps and increasing time in bed have not been found to be helpful.


Kleine–Levin Syndrome


Kleine–Levin syndrome is a rare disorder with an estimated prevalence of 1 to 2 cases per million people. Patients are mostly adolescent boys; mean age of onset is 15 years, with some rare cases beginning as early as age 9. Rare familial cases have been reported, with Ashkenazi Jews in the United States and Israel particularly affected. In a majority of cases, the first episode is triggered by a high fever or infection. Disease course typically lasts 8 to 14 years with spontaneous remission in adulthood.


The hallmark symptom of Kleine–Levin syndrome is episodic hypersomnia, with sleep time increasing to over 12 hours per day. Cognitive impairment, apathy, confusion, slowness, derealization, and amnesia are typically seen. Though not reported by all patients, hypersexuality, depressed mood, and hyperphagia may occur. Between episodes, functioning returns to normal with regard to sleep needs, cognitive functioning, and appetite.


Medically based differential diagnoses include alcohol and drug use, multiple sclerosis, temporal lobe seizures, stroke, tumor, Lyme disease, and encephalitis. Typical psychiatric differential diagnoses include depression, bipolar disease, and psychotic disorders. Many patients with Kleine–Levin syndrome first present for psychiatric evaluation.


No standard treatment has been adopted for Kleine–Levin syndrome. When given at the beginning of an episode, amantadine may help to shorten or stop an event. Lithium, lamotrigine, and valproic acid may also be beneficial. Stimulants have shown limited efficacy and may worsen behavioral and cognitive symptoms. Risperidone may help with severe cognitive changes. Family supervision is paramount during episodes. Between episodes, the patient should keep a regular sleep-wake schedule and alcohol and nicotine should be avoided.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Aug 12, 2019 | Posted by in NEUROLOGY | Comments Off on Neurologic Aspects of Sleep Medicine

Full access? Get Clinical Tree

Get Clinical Tree app for offline access