Etiology

Etiology differs according to subtype.[1][18]

  • Primary (idiopathic) central sleep apnea (CSA) has, by definition, no known etiology.

  • CSA with Cheyne-Stokes breathing (CSB) is most frequently due to congestive heart failure, renal failure, or stroke.

  • CSA due to a medical condition without CSB is secondary to a disease that is affecting the respiratory control in the central nervous system (CNS) (stroke, trauma, brainstem lesions, or demyelinating or degenerative CNS diseases).

  • CSA due to medication or substance misuse can be secondary to opioids that influence the central respiratory drive. The opioids interact with receptors on respiratory rhythm generator centers located in the ventral part of the medulla.

  • CSA due to high-altitude periodic breathing results from the hypoxemia induced by high altitude (hypobaric hypoxia), with subsequent ventilatory stimulation reaching apnea threshold during sleep.

Pathophysiology

During wakefulness, respiratory regulation involves a wakeful (voluntary) drive modulated by behavioral influences such as emotions or speech.[2] In addition, chemical (central and peripheral chemoreceptors) and mechanical (from chest wall and respiratory muscles) factors affect waking respiratory control.[2] When falling asleep, and during nonrapid eye movement (NREM) sleep, ventilatory control becomes largely regulated by the metabolic respiratory drive (chemoreceptors) in relation to the partial pressure of carbon dioxide (PaCO₂) levels. Although less well-defined, respiratory drive in rapid eye movement (REM) sleep is driven by the medial pontine reticular formation areas of REM sleep generation (“pontine neural drive”).

Sleep onset is not immediate, but rather oscillates between awake and sleep before a more stable sleep stage is reached. Furthermore, falling asleep results in decreased ventilation and a higher PaCO₂ (e.g., PaCO₂ 45 mmHg) than awake (e.g., PaCO₂ 40 mmHg). The apnea threshold is the PaCO₂ set point at (or above) which ventilation resumes and it is reset to a higher level when an individual transitions from awake to asleep. Therefore, until the CO₂ level climbs above the sleep apnea threshold while transitioning from awake to asleep, a central apnea may occur. Once the apnea threshold is reached, ventilation resumes. The ventilatory control set point is determined by hydrogen ion concentration in the cerebrospinal fluid (CSF) in contact with the ventral medullary surface, the anatomic location of the central chemoreceptors.[2][19]​ These transitional central apneas at sleep onset are common in healthy individuals, and are distinct from the recurrent pathologic central apneas that occur during sleep.

CSA syndromes are subdivided into hypercapnic and nonhypercapnic forms. Hypercapnic breathing disorders are characterized by reduced respiratory drive, or reduced neuromuscular activity (e.g., neuromuscular diseases). In nonhypercapnic forms of central apnea, respiratory drive is usually increased and/or increased chemosensitivity is present (e.g., CSA at high altitude and CSA with or without Cheyne-Stokes breathing [CSB] in CHF, stroke, or renal insufficiency). In the latter group of CSA syndromes (e.g., nonhypercapnic or hypocapnic forms), CSA can be explained by instability of the respiratory system caused by high loop gain, an excessive magnitude of respiratory drive response to a given (proportionally) minor respiratory disturbance. Loop gain has three components: circulatory time, plant gain, and controller gain. The prolonged lung to brain circulatory delay is commonly seen in CHF due to reduced cardiac output. In CHF, the circulatory delay is doubled (10-20 seconds). Controller gain is related to chemosensitivity (heightened ventilatory response to minor CO₂ fluctuations), while plant gain is related to the modification in PaCO₂ resulting from a given change in ventilation. High loop gain predisposes to hyperventilation (overshoot) and subsequent lowering of PaCO₂ below the apneic threshold. When CO₂ drops below the apneic threshold, a CSA event (undershoot) will occur and last until the CO₂ increases above the threshold. Therefore, PaCO₂ levels oscillate above and below the apneic threshold and cause the typical cyclic hyperventilation, followed by central apnea pattern that defines periodic breathing in CSB.[2]

In summary, disorders such as primary CSA, CSB, high-altitude CSA, and treatment-emergent CSA are considered to be the result of this high "loop gain" of the respiratory control system. Because of the dependence on PaCO₂ described above, these breathing disorders are generally exclusive to NREM sleep (metabolic respiratory drive).

Classification

International classification of sleep disorders in adults, American Academy of Sleep Medicine​[1]

Primary CSA

  • Idiopathic, recurrent central apneas and/or hypopneas (cessation and/or reduction of ventilation without respiratory effort) during sleep, resulting in somnolence or hypersomnia, in a person without a known medical or neurologic disorder.

CSA with Cheyne-Stokes breathing (CSB)

  • Periodic changes in the tidal volume in a crescendo-decrescendo pattern causing repetitive central apneas, and/or central hypopneas, in patients with congestive heart failure (CHF), stroke, or renal failure.

CSA due to high-altitude periodic breathing

  • Periods of central apneas and/or hypopneas alternating with periods of hyperpnea occurring during sleep, typically after ascending to altitudes of about 2500 meters (8000 feet) or above, although it is also described at lower altitudes (about 1500 meters [4900 feet]).[3]

CSA due to medical condition without CSB

  • Central apneas without characteristics of CSB occurring in people with an underlying medical or neurologic condition such as vascular, neoplastic, degenerative, demyelinating, or traumatic injury to the brainstem. Thought to be relatively rare (with the possible exception of poststroke central apnea).

CSA due to medication or substance misuse

  • Central apneas in the form of ataxic breathing (variable length of CSAs and respiration rate) or intermittent and sporadic central apneas, secondary to intake of opioids or other known respiratory depressant (e.g., ticagrelor).

Treatment-emergent CSA

  • Diagnostic sleep study, polysomnography (PSG) during use of positive airway pressure shows significant resolution of obstructive respiratory events (e.g., obstructive or mixed apneas or hypopneas) and emergence or persistence of central apnea or central hypopnea.

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