Contemporary Sleep Medicine For Physicians

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Sleep is defined as a reversible state of reduced responsiveness to environmental stimuli. It roughly occupies one third of a human life. The science of sleep has greatly evolved over the past century. From a state of passive inactivity, sleep has come to be regarded as a complex physiologic state, with characteristic brain activity.

The neurobiology of sleep is complex. Transection studies have led to the description of the ascending reticular activating system as responsible for the awake state, with the main neurotransmitters involved being acetylcholine, norepinephrine, glutamate, serotonin, dopamine, histamine and orexin. Similarly, specific brain regions have been involved in the active generation of sleep. Non rapid eye movement (NREM) sleep is generated in the basal forebrain and anterior hypothalamus, containing the neurotransmitters gamma amino butyric acid (GABA) and galanin. These areas send inhibitory signaling to the excitatory regions of the brain. Rapid eye movement sleep (REM) is generated in the caudal pons and rostral mesencephalon area. It consists of several features, divided into tonic and phasic phases. Each of these is produced by a specific group of neurons. Acetylcholine is one of the major neurotransmitters in REM sleep.

Sleep has been described in the developing human fetus as early as 28 weeks of gestation. At birth, the human infant sleeps up to 16-18 hours a day and spends half of that time in REM sleep. This high fraction of sleep in the human infant has led to the hypothesis that REM is important in brain maturation.

Obstructive sleep apnea (OSA) is estimated to affect about 24% of adult males and 9% of adult females. The prevalence rate of OSA with excessive daytime sleepiness was reported to be 5-7 % in adult males and 3-4 % in adult females. Since these publications, the incidence and prevalence of obesity, a major risk factor for OSA, has increased significantly.

Central sleep apnea (CSA)m is a conglomerate of different conditions, including: primary CSA, Cheyne-Stokes breathing-CSA (CSB-CSA) pattern, high-altitude periodic breathing, CSA due to medical conditions not Cheyne- Stokes, and CSA due to drugs or substances. Another newly recognized CSA syndrome is complex sleep apnea, which is seen during treatment of OSA, generally before the obstructive events are completely abolished by positive airway pressure (PAP). Primary CSA is uncommon in adults and is seen in less than 10% of patients presenting polysomnography (PSG). The prevalence of primary CSA, high-altitude periodic breathing, and CSA due to medical conditions in the general population are unknown. The obesity-hypoventilation syndrome (OHS) is also known as obesity-associated hypoventilation or Pickwickian syndrome. Criteria for OHS includes a BMI ≥ 30 kg/m2 and chronic alveolar hypoventilation leading to daytime hypercapnia, in the absence of pulmonary or neuromuscular disease.

Epidemiological data on insomnia has been confounded by multiple definitions; most of the studies account for three insomnia symptoms: difficulty falling asleep, difficulty maintaining sleep and early morning awakenings. Insomnia symptoms were reported to be present in about one-third of the general population. Non-restorative sleep, which is also part of the insomnia definition (ICSD-2), is rarely explored. When daytime consequences of insomnia are taken into account, the prevalence is estimated to be around 10%. Overall, daytime consequences may be as prevalent as 2/3 of insomnia subjects.

Narcolepsy is classically defined by sleepiness and abnormal rapid eye movement (REM) sleep-related symptoms (cataplexy, hypnagogic hallucinations, and sleep paralysis). In one study, the prevalence of narcolepsy with or without cataplexy has been reported as 30.6 per 100,000 people (18 years or older), narcolepsy with cataplexy as 21.8/ 100,000 people and narcolepsy with HLA-DQB1 *0602 as 15.3/ 100,000 people. In 18,980 randomly selected subjects, representative of a target population of 205 million European inhabitants, excessive daytime sleepiness was reported by 15% of the sample, napping two times or more in the same day was reported by 1.6% of the sample, while cataplexy (episodes of loss of muscle function related to a strong emotion) was found in 1.6% of the sample. A narcolepsy diagnosis was reported in 47/100,000 people, severe for 26/100,000 and moderate in 21/100,000. Multiple sleep-onset REM periods and short mean sleep latencies (of less than 8 minutes) were reported in about 4% of the general population.

Patients afflicted with sleep disorders may have a wide variety of complaints, the majority of which are, generally, nonspecific. It is therefore critically important that providers caring for these patients should be well-versed in the appropriate work-up of snoring, daytime sleepiness, insomnia and nocturnal behaviors. This chapter will briefly review these common complaints and the appropriate evaluation of each.

Sleep testing has evolved over the years and today sleep testing is considered among some of the most sophisticated medical testing modalities. Although the most common sleep test used today is diagnostic polysomnogram, which is generally employed to diagnose sleep apnea, sleep testing today is much more than just-a-tool to diagnose sleep disordered breathing. Various sophisticated tests, with highly standardized processes and technologies, in association with precise diagnostic criteria backed by extensive scientific data, are conducted every day in various sleep centers across the country and the world. The fast pace of technological advancements in this field continues to provide new breakthroughs in the acquisition of various sleep-related physiological variables every day.

Although a nocturnal polysomnogram (PSG) is often used synonymously with the term “sleep test“, well-staffed and competent sleep centers are capable of performing a wide array of sleep studies, including: diagnostic PSGs (typically to diagnose sleep apnea), titration studies (e.g., to obtain optimal positive airway pressure setting to treat sleep apnea), PSGs with extended EEG montages (e.g., to diagnose co-existent seizures), PSGs with extended limb leads and video monitoring (e.g., to diagnose REM sleep behavior disorder, etc), nocturnal penile tumescence (NPT, to diagnose erectile impotence), actigraphy tests, etc.

Snoring is a common phenomenon and results from vibration of the soft tissue structures in the upper airway. Snoring may occur alone or as a sign of upper airway resistance syndrome (UARS) or obstructive sleep apnea syndrome (OSA). Snoring carries social consequences and has been linked to increased risk for cardiovascular disease, although this relationship may be confounded by undiagnosed OSA. UARS is characterized by daytime dysfunction and repetitive respiratory effort-related arousals, episodes of increasingly intense breathing efforts that terminate with an arousal from sleep before a hypopnea (episode of partial airflow reduction) or apnea (episode of complete airflow reduction) occur. There is controversy whether UARS is a distinct clinical entity or part of the OSA spectrum. Long-term cardiovascular consequences of UARS are unclear. Risk factors for snoring and UARS are similar and include obesity, nasal congestion, ingestion of pharyngeal relaxing substances before bed such as alcohol, hypnotics, and skeletal muscle relaxants, and abnormalities of the bony and soft tissue structures of the head and neck. Treatment options for snoring and UARS overlap and include risk factor modifications, oral appliances to advance the mandible during sleep, continuous positive airway pressure, and upper airway surgeries.

Obstructive sleep apnea (OSA) is a condition characterized by repeated episodes of apnea and hypopnea (partial apnea) during sleep. Characteristic symptoms include loud snoring, witnessed apneas, gasping and choking sensations at night, nocturnal awakenings resulting in poor sleep quality, fragmented sleep and excessive daytime sleepiness. Polysomnography is the “gold standard” test for the diagnosis of OSA. The number of apneas and hypopneas per hour of sleep (apnea-hypopnea index, AHI) is the metric most commonly used to determine the severity of OSA. AHI between 5 and 14 represents mild OSA, between 15 and 29 moderate OSA and 30 or higher is severe OSA. Continuous Positive Airway Pressure (CPAP) is the preferred option for the treatment of moderate to severe OSA and optional for mild OSA.

Central sleep apnea (CSA) is a sleep-related breathing disorder that is characterized by repetitive cessation of airflow due to diminished or absent ventilatory effort. There are several types of CSA, and these can be classified into two general types, namely hypercapnic (central alveolar hypoventilation, secondary to neuromuscular disorders or chronic use of long-acting opioids) or non-hypercapnic forms (idiopathic CSA, CSA due to heart failure, sleep-onset periodic breathing, high-altitude central apneas, and continuous positive airway pressure-emergent CSA). Whatever its cause(s), CSA can give rise to sleep disturbance, repetitive awakenings, insomnia or excessive sleepiness. Definitive diagnosis of CSA requires polysomnography. Therapy should be individualized depending on the nature and severity of central apnea; this may include use of oxygen supplementation, drug therapy or positive airway pressure.

Obesity Hypoventilation syndrome (OHS) is defined as the triad of obesity, daytime hypoventilation, and sleep disordered breathing in the absence of an alternative explanation for hypoventilation. Among patients with obstructive sleep apnea (OSA), those who are more obese and have more severe OSA are more likely to have the syndrome. It is unclear why some patients with OSA develop OHS and others do not. It is important to identify the syndrome early, as these patients may have a significantly increased risk of mortality if left untreated. The authors describe current understanding of the pathogenesis of the disorder and optimal treatment modalities.

Insomnia is a common health complaint that produces a significant impairment in quality of life and involves difficulty in initiating sleep, maintaining sleep, waking too early, non-restorative sleep, and daytime functional deficits. Insomnia is associated with a disturbance in one or more of the three systems that regulate sleep: homeostatic, circadian and arousal. A disturbance may result from genetic/dispositional issues, from acute life events, from habitual behaviors and attitudes, or from any combination of these three types of issues. A number of treatment methods have been developed that use behavior modification and cognitive restructuring to facilitate homeostatic and circadian mechanisms of sleep, and to reduce arousal during bedtime. These methods actively engage the patient to implement life style changes, attitudes and beliefs that promote sleep.

Suprachiasmatic nucleus is the master circadian clock that regulates various endogenous circadian rhythms. Light and social cues are important factors that help align the endogenous circadian rhythms to the 24 hour day. Circadian rhythm sleep disorders can be due to abnormalities in the endogenous circadian clock (“intrinsic disorders”) such as delayed sleep phase type, advanced sleep phase type, free running type, and irregular sleep wake rhythm type. Shift work or air travel leads to an artificial mismatch between the endogenous circadian clock and the external environment (“extrinsic disorders”) leading to shift work disorder and jet lag disorder. Individuals with circadian rhythm sleep disorders are presented with insomnia or excessive sleepiness or both.

These disorders are under recognized in the general population but they can affect a significant number of people if a the large number of shift workers and air travelers are considered. The symptoms may be misdiagnosed for other common sleep disorders such as sleep apnea or insomnia. Meticulous history and sleep diary data are integral tools in diagnosing CRSD. Actigraphs (activity monitors) may supplement the sleep diary data. In the past two decades major advances have been made in understanding the genetic basis of these disorders. Understanding the circadian principles has led to various therapeutic options such as phototherapy and exogenous melatonin.

Narcolepsy with and without cataplexy has two different nosological entities. Narcolepsy-cataplexy is strongly associated with HLA-DQB1*0602 and usually caused by a selective deficiency in the hypothalamic neuropeptide hypocretin (orexin). The cause of hypocretin deficiency is most likely an autoimmune attack directed against hypocretin cells. Diagnosis is performed clinically, with the additional sleep tests such as the Multiple Sleep Latency Test, or in some cases, by measuring hypocretin-1 levels in the Cerebrospinal fluid (CSF).< /p> < p>To date, therapy is mostly pharmacological and does not act directly on the hypocretin system. Stimulant compounds seem to increase alertness by activating dopaminergic transmission in the brain, while antidepressant therapy reduces cataplexy by increasing adrenergic and serotoninergic transmission. The mode of action of gamma-hydroxybutyrate (sodium oxybate), a treatment for cataplexy and disturbed nocturnal sleep is uncertain, but may involve GABA-B receptors. Narcolepsy without cataplexy is primarily diagnosed using MSLT, with a finding of a short mean sleep latency (≤ 8 min) and at least 2 Sleep Onset REM Periods (SOREMPs). The population-based prevalence of narcolepsy without cataplexy is unknown. It is likely that many cases of narcolepsy without cataplexy have very different pathogenesis, and/or result from false-positive MSLT. A minority of cases without cataplexy have hypocretin deficiency. For cases without cataplexy or hypocretin deficiency, research is needed to better understand the pathophysiology. Therapy is similar to that used for cases with cataplexy, although amphetamine stimulants should be used with more caution.

Idiopathic hypersomnia is a primary sleep disorder of central nervous system origin. It is an uncommon sleep disorder. However, it impacts patients significantly in their day to day activity. It is seen less frequently than narcolepsy. It is described clinically with excessive daytime sleepiness, often prolonged episodes of non-refreshing sleep, prolonged naps and difficulty in awakening from sleep. The difficulty awakening from sleep is often labeled as “sleep drunkenness”. At this time, the pathophysiology of this disorder is not well understood. It is very important to exclude other potential causes and therefore is a diagnosis of exclusion. Treatment for this disorder is in the similar algorithm as patients with narcolepsy; however the response is not consistent. Therefore, this specific disorder is one of the frustrations for most clinicians who treat these patients. This section will review the epidemiology, pathogenesis, clinical features, diagnostic criteria, differential diagnosis, treatment and future outlook of this frustrating disorder.

Under normal circumstances, movement is relatively suppressed during sleep. Motor system activity reflects this paucity of movement as it decreases from drowsiness to slow wave sleep (SWS) and then further in rapid eye movement (REM) sleep. Some movement during sleep in fact is adaptive with small shifts in body weight preventing pressure-related injuries such as nerve palsy and skin ulceration. Other movements occurring during sleep serve no obvious purpose and may even fragment sleep, especially when recurrent. This latter constellation of movements constitutes the sleep-related movement disorders. This chapter will focus on the sleep-related movement disorders which are largely characterized by repetitive, non-epileptic, purposeless movement which occurs during sleep. Many of the sleep-related movement disorders are clinically benign or on the severe end of the normal spectrum and as such our discussion will begin with an introduction to normal movement during sleep. The chapter continues with a discussion of benign sleep-related movement then the clinically recognized sleep-related movement disorders. Special attention will be given to restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) as these entities are both common and a major source of morbidity.

Parasomnias are any undesirable physical events or experiences that happen during falling asleep, staying asleep or during arousals from sleep. Parasomnias are classified primarily based on the stage of sleep from which they originate i.e. NREM or REM sleep and by the nature of symptoms, i.e. sleep terrors, sleep walking, sleep eating, etc. These disorders vary both in frequency and severity and range from relatively benign events such as occasional episode of sleep paralysis to potentially serious and sometimes life-threatening events such as REM sleep behavior disorder. Parasomnias are also considered to be automatisms since the subjects sometimes do not have conscious awareness during these episodes resulting in some medico-legal consequences. Parasomnias can significantly affect the quality of sleep resulting in daytime impairments and they can also affect sleep and safety of the bed-partners. However, a thorough clinical assessment, appropriate tests where indicated, and judicious use of medications can help a vast majority of patients with parasomnia disorders.

Advances in science and technology over the last century have resulted in a steady increase in the average life expectancy of human beings, especially in developed countries. This trend implies a gradual increase in the proportion of older adults in the general population and that this group of the population will account for an increasing and significant proportion of patients seen by physicians in most clinical disciplines in the near future. For this reason, understanding the aging process and associated changes that occur in the different organs and systems is of paramount importance. Accordingly, age-related changes occur in sleep and wake system and these are described below.

Sleep is essential for optimal mental, physical and social wellbeing (or, generically, health). Sleep disruption and/or deprivation can have adverse health consequences, promoting or worsening cardiovascular disease and diabetes. The sleep-wake cycle is a very tightly regulated process that involves multiple neuropharmacological reciprocal interactions. It was recently shown that sleep deprivation and sleep disorders can have adverse metabolic consequences. Multiple medications have a direct or indirect impact on sleep and the waking state. In this article, we review the effects of commonly prescribed medications on the sleep-wake cycle.

Sleep has always been associated with the overall concept of health. Over the past decades, the association between sleep and cardiovascular diseases has been emerging. Several sleep disorders are now known to be associated with cardiovascular disease. One of the most notorious associations is with obstructive sleep apnea (OSA). OSA has been linked to a higher incidence of hypertension, with up to 50% of patients with OSA having an elevated blood pressure. Continuous Positive Airway Pressure (CPAP) treatment has been shown to improve blood pressure. The pathogenesis of hypertension in OSA is related to the sympathetic nervous system activation (SNA) that occurs following each apneic episode and that requires the presence of intermittent hypoxia. OSA is similarly linked to an increased risk of cardiac ischemia as well as congestive heart failure.

Treatment with CPAP can improve cardiovascular mortality and left ventricular ejection fraction. OSA is also associated with arrhythmias and strokes. Central sleep apnea and Cheyne Stokes respiration have been described in patients with congestive heart failure and their presence could lead to a worse prognosis. CPAP treatment improves ejection fraction but the effect on mortality has not been proven. Other sleep disorders are linked to increased cardiovascular risk. These include insomnia, short and long sleep duration, circadian rhythm disorders and possibly restless leg syndrome. Sympathetic activation in the form of elevated norepinephrine levels has been documented in patients with OSA. Other markers studied include inflammatory markers and markers of oxidative stress. Although a lot of progress has been made, a specific molecular signature for OSA is yet to be found.

On average, human beings spend approximately one third of their life sleeping. Many individuals are chronically sleep deprived, while many individuals with primary sleep illnesses, such as obstructive sleep apnea (OSA) are unaware of their condition; as a result, without treatment, they suffer from serious negative physical, neurobehavioral and metabolic consequences. Obstructive sleep apnea is now a well recognized chronic disorder that leads to multiple cardiovascular and metabolic complications.

During the last decades there has been a mounting body of data that established a better characterized link between OSA and insulin resistance, diabetes mellitus and/or metabolic syndrome. Likely mechanistic mediators of this connection are intermittent hypoxia and sleep fragmentation. Through sympathetic system activation, oxidative stress, hypoxia/re-oxigenation, systemic inflammation, production of harmful adipokines from metabolically active visceral fat and complex endocrine changes, sleep apnea and obesity lead to a vicious cycle of abnormal glucose metabolism, which likely contributes to an increase in cardiovascular morbidity and mortality. When appropriate, physicians should have a low threshold to assess sleep apnea, as effective therapy is readily available (CPAP, mandibular advancement devices, etc). In this chapter we will summarize and analyze the most current data in this rapidly growing field of sleep medicine.

When considered separately from cardiovascular disease, stroke is the third leading cause of death and ranks as the leading cause of long-term disability [1]. Strategies for stroke treatment and prevention have helped to reduce the burden of disease, but it remains an important public health challenge. Therefore, understanding underlying pathophysiology and developing novel therapeutic approaches for cerbrovascular disease is of crucial importance.

Understanding the link between sleep and cerebrovascular disease may represent one such novel approach. A recent Institute of Medicine report, entitled Sleep Disorders and Sleep Deprivation: an Unmet Public Health Challenge, estimated that 50-70 million Americans suffer from a chronic sleep disorder. A major aspect of this “unmet public health challenge” is the cerebrovascular health consequences of sleep-disordered breathing. Obstructive sleep apnea (OSA), a common form of sleep-disordered breathing, has a high and rising prevalence in the general adult population, attributable in part to the emerging epidemic of obesity and enhanced awareness. OSA has also been independently linked to important health outcomes, including hypertension [2], fatal and nonfatal cardiovascular events [3-5], stroke [6-8], sudden cardiac death [5] and all cause mortality [9, 10], while therapy for sleep apnea may help to reduce cerebrovascular risk.

Over a century of work has confirmed critical links between sleep and epilepsy. Seizures can have profound effects on sleep, typically causing awakenings, arousals and shifts to lighter stages. However, sleep continuity is disrupted in people with epilepsy even in the absence of seizures, suggesting that sleep instability may be an inherent component of certain forms of epilepsy. Antiepileptic drugs (AEDs) can adversely affect sleep and wakefulness. At least some of the newer AEDs appear to have more favorable sleep-wake profiles than the older agents. In turn, sleep is an important modulator of seizures and epileptic discharges on the electroencephalogram (EEG). Sleep instability can promote seizures and sleep deprivation provokes seizures and EEG abnormalities. Synchronized Non-REM (NREM) sleep facilitates seizures, whereas the clinical and EEG manifestations of epilepsy are suppressed in REM sleep. The sleep EEG is useful in the diagnosis and localization of epilepsy. New epileptic foci can appear in sleep and REM sleep demonstrates the most precise localization of the epileptic discharge. Polysomnography combined with video and EEG (VEEG-PSG) aids in the differentiation of seizures and parasomnias. Daytime sleepiness and sleep disorders such as sleep apnea are common in people with epilepsy. Treating sleep apnea has been shown to reduce EEG abnormalities and seizures in some cases. These observations underscore the importance of a routine sleep assessment in case of all the people with epilepsy.

Pediatric sleep disorders are quite common and often disturbing to either the patient or the child's family. As the patient matures into adult, sleep disorders continue to be common and an important factor in development, both social and cognitive. Sleep disorders can adversely impact physical and mental health. Nonrestorative sleep can hamper a child's ability to concentrate and control emotions and behavior. Sleep disorders vary among age groups, but most can occur with varying frequency at any age.

Several disorders are typically seen only during the first few years of life, including colic, excessive nighttime feedings, and sleep onset association disorder. A number of conditions are common during childhood but begin to improve as the child ages. The non-REM sleep parasomnias, including sleepwalking, confusional arousals, and night terrors, are the most common in the pediatric category. Nightmares are also common in childhood but can occur at any age.

Sleep-related breathing disorders including obstructive sleep apnea, central sleep apnea, central alveolar hypoventilation syndrome, and Cheyne-Stokes respirations are not found only in adults but are, in fact, quite common in the pediatric population. While these disorders can occur at any age, treatment options vary substantially by age.