INTRODUCTION — Central sleep apnea (CSA) is a disorder characterized by repetitive cessation or decrease of both airflow and ventilatory effort during sleep. CSA is less common than obstructive sleep apnea (OSA) and is often associated with other medical conditions, especially heart failure, stroke, and opioid medications. Rare cases are primary or idiopathic.
CSA can alternatively be categorized as hyperventilation- or hypoventilation-related. Hyperventilation-related CSA encompasses most of the types of CSA mentioned above; a notable exception is CSA associated with a drug or substance. Hypoventilation-related CSA occurs in disorders in which there is alveolar hypoventilation that is so severe that central apneas occur when the patient falls asleep because the wakefulness stimulus to breathe disappears. Central apneas tend to be a minor component of such disorders. Examples of contexts in which hypoventilation-related CSA may occur include central nervous system diseases, central nervous system suppressing drugs or substances, neuromuscular diseases, and severe abnormalities in pulmonary mechanics (eg, kyphoscoliosis). (See "Central sleep apnea: Pathogenesis", section on 'Hyperventilation-related central apnea' and "Central sleep apnea: Pathogenesis", section on 'Hypoventilation-related central apnea'.)
The clinical presentation and diagnosis of hyperventilation-related CSA are reviewed here. Hypoventilation-related CSA is not discussed here because central apneas tend to be a minor component of the underlying condition and, therefore, the presentation and diagnosis are dictated by the underlying condition. The pathogenesis and treatment of CSA are discussed separately. (See "Central sleep apnea: Pathogenesis" and "Central sleep apnea: Treatment".)
EPIDEMIOLOGY — CSA is common, although less prevalent in the general population than obstructive sleep apnea (OSA). In a population-based study that included 5804 community-dwelling adults aged 40 years and older, the overall prevalence of CSA on polysomnography was 0.9 percent [1]. Approximately half of the CSA cases were associated with Cheyne-Stokes breathing (0.4 percent overall). The median age of patients with CSA was 69 years. CSA was more common among patients with heart failure (4.8 percent) and in males compared with females (1.8 versus 0.2 percent).
RISK FACTORS — The prevalence of symptomatic CSA (ie, CSA syndrome) appears to be higher among older adults, males, those with certain comorbid medical conditions such as heart failure, and patients who chronically use opioids [2,3].
Age — The prevalence of CSA syndrome is greater among adults who are older than 65 years than among younger adults (1.1 versus 0.4 percent), according to an observational study of 741 randomly selected adults that defined CSA syndrome as a central apnea-hypopnea index ≥10 events per hour plus symptoms or signs of disrupted sleep (eg, daytime sleepiness) [4]. The study also found that 12 percent of the adults older than 65 years had ≥2.5 central apneas per hour of sleep compared with only 1.7 percent of younger adults.
The increased prevalence of CSA syndrome among older adults may reflect the higher frequency of comorbid conditions that influence breathing during sleep among older adults, such as heart failure [5], atrial fibrillation [6], and cerebrovascular diseases [7,8]. Alternatively, it may be due to the aging process itself or to sleep state oscillation precipitating central apnea [9]. (See "Central sleep apnea: Pathogenesis", section on 'Sleep-onset central apneas'.)
Sex — CSA syndrome is more prevalent among males than females. In one population-based sample, the prevalence of CSA syndrome was 0.4 percent among males and 0 percent among females, while central apneas were detected in 7.8 percent of males and only 0.3 percent of females [10]. Experimentally, the propensity for developing hypocapnic central apnea is greater in males compared with females [11]. (See "Central sleep apnea: Pathogenesis".)
The difference in CSA propensity between sexes may relate to the effects of both testosterone and estrogens on apneic threshold. Administration of testosterone to healthy premenopausal females for 12 days increases the apneic threshold during non-rapid eye movement (NREM) sleep [12], whereas suppression of testosterone with leuprolide acetate in healthy males decreases the apneic threshold [13]. In a separate study, there was no difference in carbon dioxide reserve between males and postmenopausal females during NREM sleep, whereas administration of hormone replacement therapy in females increased carbon dioxide reserve (reflecting lower susceptibility to central apnea) [14].
Heart failure — Both CSA associated with Cheyne-Stokes breathing, and obstructive sleep apnea (OSA) are prevalent among patients with heart failure [5,15-17]. The former is particularly common among individuals with heart failure who are male, older than 60 years, have atrial fibrillation, or have daytime hypocapnia (PaCO2 <38 mmHg) [18]. CSA and OSA in patients with heart failure are reviewed in detail separately. (See "Sleep-disordered breathing in heart failure".)
Stroke — CSA is common after stroke [7,19]. This was illustrated by a prospective cohort study of 161 patients who had a stroke. Approximately 70 percent of patients developed sleep apnea (defined as an apnea-hypopnea index >10 events per hour) within the initial 72 hours, including 26 percent with CSA in the context of Cheyne-Stokes breathing. Three months later, CSA was detected in only 7 percent of the patients, suggesting that CSA following acute stroke is often self-limited. There was no relationship between the location of the stroke and the likelihood of sleep apnea. The diagnosis and management of sleep apnea in patients with stroke is discussed in more detail elsewhere. (See "Sleep-related breathing disorders and stroke".)
Other medical conditions — CSA appears to be common among patients with certain medical conditions, including acromegaly [20,21], renal failure [22], atrial fibrillation [2,23], low cervical tetraplegia [24], and primary mitochondrial diseases [25].
Medications — CSA occurs with increased frequency in patients who chronically use opioids, including methadone maintenance therapy. Concomitant benzodiazepines, which blunt the arousal response to hypoxia and hypercapnia during sleep, antidepressants, and gabapentinoid drugs may be associated with increased risk. High doses of baclofen have also been associated with CSA through central nervous system depressant effects [26]. (See "Sleep-disordered breathing in patients chronically using opioids".)
Other medications may increase the activity of respiratory centers or generate respiratory instability, resulting in or aggravating hyperventilation-associated CSA [3]. There are rare reports of CSA associated with ticagrelor, a P2Y12 receptor antagonist, possibly through an effect on pulmonary C fibers [3,27-30].
CLINICAL FINDINGS — The clinical features of CSA may be elucidated by a medical history, physical examination, or routine inpatient monitoring.
Clinical presentation — Patients with CSA typically present with symptoms of disrupted sleep, such as excessive daytime sleepiness, poor subjective sleep quality, insomnia, inattention, and poor concentration. They may also report symptoms due to the recurrent central apneas with oxyhemoglobin desaturation, including paroxysmal nocturnal dyspnea, morning headaches, and nocturnal angina. These may be the presenting complaints, reported during the evaluation of another complaint, or detected during health maintenance screening. Alternatively, CSA may be first suspected when a hospitalized patient is being monitored and is noted to have episodic oxyhemoglobin desaturation, pauses in breathing, or nocturnal arrhythmias. (See "Obstructive sleep apnea and other sleep disorders in hospitalized adults", section on 'Central sleep apnea'.)
History — Excessive daytime sleepiness is a common feature of CSA. However, it may go unnoticed or its significance may be underestimated because of its insidious onset and chronicity. Therefore, careful questioning is essential to uncover subtle drowsiness in boring, passive, or monotonous situations, such as driving, watching television, and reading. Excessive daytime sleepiness may not be present and is not a required feature of CSA, as some patients complain instead of insomnia due to the repetitive awakenings.
In addition to daytime sleepiness, the clinician should ask about other symptoms of disrupted sleep, such as poor subjective sleep quality, fatigue, inattention, poor concentration, moodiness, decreased libido, and impotence. Patients may complain of paroxysmal nocturnal dyspnea due to the compensatory hyperpnea that follows a central apnea, or they may report morning headaches and nocturnal angina due to the episodic oxyhemoglobin desaturation. Bed partners may report apneic periods.
CSA is typically associated with another medical condition and, therefore, patients often report the symptoms of the coexisting condition. As an example, patients with CSA associated with Cheyne-Stokes breathing may report symptoms of heart failure, such as dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea. When the CSA occurs in the context of Cheyne-Stokes breathing, the bed partner may report episodic hyperpnea, hypopnea, and apneic periods.
Physical examination — There are no physical findings that are specific for CSA. However, patients who have CSA associated with another condition typically have physical findings due to the associated condition. As examples, patients with CSA associated with Cheyne-Stokes breathing due to heart failure frequently have peripheral edema, crackles, an S3 gallop, jugular venous distension, or right upper quadrant pain due to hepatic congestion, while patients with CSA associated with stroke may have asymmetric weakness, sensory or cranial nerve abnormalities, or ataxia. Many patients with CSA have an irregularly irregular pulse due to atrial fibrillation [6].
Monitoring data — Hospitalized patients who are being monitored may exhibit abnormalities due to CSA. Among the more common monitoring abnormalities are episodic apneic periods detected by a respiratory monitor, episodic oxyhemoglobin desaturation detected by continuous pulse oximetry, atrial fibrillation detected by telemetry while the patient is asleep or awake, and nocturnal arrhythmias detected by telemetry. While such monitoring data are not specific enough to confirm or exclude CSA, they warrant consideration of CSA, particularly when risk factors for CSA exist.
DIAGNOSTIC EVALUATION — Patients with daytime sleepiness plus risk factors for CSA (eg, heart failure, stroke, use of a long-acting opioid) or more than one symptom or sign of CSA (eg, daytime sleepiness, insomnia, morning headaches, nocturnal angina, witnessed pauses in breathing during sleep) should undergo full-night, attended, in-laboratory polysomnography (PSG). PSG is considered the gold standard diagnostic test for sleep-related breathing disorders. Ambulatory diagnosis and management, including home sleep apnea testing, have not been validated for the management of CSA.
During PSG, the patient is connected to a variety of monitoring devices. Physiologic variables are recorded digitally on a paperless computerized system while the patient sleeps and during any intervening wakefulness. Captured information includes sleep stages (via electroencephalography, electrooculography, submental electromyography), respiratory effort (usually via respiratory inductive plethysmography, sometimes with electromyography, strain gauges, piezo electrodes, or impedance devices), airflow (usually via a nasal pressure transducer and oronasal thermistor), oxyhemoglobin saturation (via continuous pulse oximetry), and heart rate and rhythm (via continuous electrocardiography). The sleeping room is usually equipped with an infrared camera and audio system that allows the technologist to see, hear, and communicate with the patient without entering the bedroom. Patterns of physiologic abnormalities during sleep are often diagnostic. (See "Overview of polysomnography in adults" and "Polysomnography in the evaluation of sleep-disordered breathing in adults".)
DIAGNOSTIC CRITERIA — The diagnostic criteria for CSA vary according to the type of CSA [31]:
●Primary CSA requires the following four findings:
•Polysomnography (PSG) reveals ≥5 central apneas and/or central hypopneas per hour of sleep; the number of central apneas and/or central hypopneas is >50 percent of the total number of apneas and hypopneas; and there is no evidence of Cheyne-Stokes breathing.
•The patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep).
•There is no evidence of daytime or nocturnal hypoventilation.
•The disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use, or substance use disorder.
●CSA with Cheyne-Stokes breathing requires the following four findings:
•PSG reveals ≥5 central apneas and/or central hypopneas per hour of sleep; there are at least three consecutive central apneas and/or central hypopneas separated by crescendo-decrescendo breathing with a cycle length of at least 40 seconds (ie, Cheyne-Stokes breathing pattern) [32]; and the number of central apneas and/or central hypopneas is >50 percent of the total number of apneas and hypopneas.
•The patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep).
•The breathing pattern is associated with atrial fibrillation/flutter, congestive heart failure, or a neurological disorder.
•The disorder is not better explained by another current sleep disorder, medication use (eg, opioids), or substance use disorder.
●CSA due to high altitude periodic breathing requires the following four findings:
•Recent ascent to a high altitude (typically at least 2500 meters, although some individuals may exhibit the disorder at altitudes as low as 1500 meters).
•The patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep).
•Symptoms are clinically attributable to high-altitude periodic breathing or PSG, if performed, reveals recurrent central apneas or hypopneas primarily during non-rapid eye movement (NREM) sleep at a frequency of ≥5 per hour.
•The disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use (eg, narcotics), or substance use disorder.
●CSA due to a medication or substance requires the following four findings:
•The patient is taking an opioid or other respiratory depressant
•The patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep).
•PSG reveals ≥5 central apneas and/or central hypopneas per hour of sleep; the number of central apneas and/or central hypopneas is >50 percent of the total number of apneas and hypopneas; and there is no evidence of Cheyne-Stokes breathing.
•The disorder is not better explained by another current sleep disorder.
Central apneas and hypopneas are defined separately. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults".)
DIFFERENTIAL DIAGNOSIS — A variety of conditions must be considered in the differential diagnosis of CSA because they similarly cause excessive daytime sleepiness and other symptoms and signs of disrupted sleep. All of these conditions are distinguished via polysomnography:
●Obstructive sleep apnea (OSA) – OSA is a disorder that is characterized by repetitive obstructive apneas and hypopneas caused by complete or partial collapse of the upper airway during sleep. These obstructive events typically lead to awakenings, resulting in symptoms and signs of disrupted sleep. Among the disorders in the differential diagnosis of CSA, OSA is the most closely related because only CSA and OSA are characterized by symptoms and signs of episodic oxyhemoglobin desaturation (eg, morning headaches). (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Management of obstructive sleep apnea in adults".)
●Periodic limb movements of sleep (PLMS) – PLMS are recurrent jerks of the legs and arms that can occur in association with arousals. When PLMS are excessive, symptoms can include insomnia or daytime sleepiness. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)
●Rotating shift workers – Night-shift workers obtain approximately seven hours per week less sleep than non-shift workers. They often revert to a daytime schedule on their leisure days, which adds to their sleep deprivation and daytime sleepiness.
●Narcolepsy – Narcolepsy is a clinical syndrome of excess daytime sleepiness. Additional features may include cataplexy, hypnagogic hallucinations, sleep attacks (episodes of sudden need to lie down and sleep), and sleep paralysis. Although these additional features are classically described, a wide spectrum of clinical presentations exists [33]. (See "Clinical features and diagnosis of narcolepsy in adults" and "Treatment of narcolepsy in adults".)
●Respiratory disease – Patients with either chronic obstructive lung disease or restrictive lung disease may have sleep-related hypoventilation with desaturation, resulting in sudden awakenings and dyspnea that imitate CSA. Patients with neuromuscular disease depend on their accessory muscles to breathe and the inhibition of muscle activity during rapid eye movement (REM) sleep can cause hypoventilation with profound desaturations and awakenings. Poorly controlled asthma is often worse at night, with nocturnal bronchospasm and cough inducing sleep fragmentation and paroxysmal dyspnea.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sleep-related breathing disorders in adults".)
SUMMARY AND RECOMMENDATIONS
●Central sleep apnea (CSA) is a disorder characterized by repetitive cessation or decrease of both airflow and ventilatory effort during sleep. It can be primary (ie, idiopathic CSA) or secondary. Secondary CSA can occur, for example, in association with Cheyne-Stokes breathing, a medical condition, a drug or substance, or high altitude periodic breathing. (See 'Introduction' above.)
●CSA is uncommon in the general population; however, its prevalence is higher among older adults, males, and those with certain comorbid conditions, such as heart failure or stroke. (See 'Risk factors' above.)
●Patients with CSA typically present with symptoms of disrupted sleep (eg, excessive daytime sleepiness, poor subjective sleep quality, insomnia, inattention, and poor concentration) and/or symptoms due to recurrent central apneas with oxyhemoglobin desaturation (eg, paroxysmal nocturnal dyspnea, morning headaches, and nocturnal angina). These may be the presenting complaints, reported during the evaluation of another complaint, or detected during health maintenance screening. Alternatively, CSA may be first suspected when a hospitalized patient is being monitored and is noted to have episodic oxyhemoglobin desaturation, pauses in breathing, or nocturnal arrhythmias. (See 'Clinical presentation' above.)
●Patients with daytime sleepiness plus risk factors for CSA (eg, heart failure, stroke, chronic opioid therapy) or more than one symptom or sign of CSA (eg, daytime sleepiness, insomnia, morning headaches, nocturnal angina, witnessed pauses in breathing during sleep) should undergo full-night, attended, in-laboratory polysomnography (PSG). PSG is considered the gold standard diagnostic test for sleep-related breathing disorders. (See 'Diagnostic evaluation' above.)
●The diagnostic criteria for CSA vary according to the type of CSA. Generally speaking, diagnosis generally requires evidence of frequent central apneas via polysomnography, symptoms or signs of disrupted sleep, association with an underlying cause, and exclusion of alternative diagnoses. (See 'Diagnostic criteria' above.)
●A variety of conditions must be considered in the differential diagnosis of CSA because they similarly cause excessive daytime sleepiness and other symptoms and signs of disrupted sleep. All of these conditions are distinguished by polysomnography. They include obstructive sleep apnea, periodic limb movements of sleep, shift work, narcolepsy, and respiratory disease. (See 'Differential diagnosis' above.)
