Aetiology

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

  • Primary (idiopathic) central sleep apnoea (CSA) has, by definition, no known aetiology.

  • 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 centres located in the ventral part of the medulla.

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

Pathophysiology

During wakefulness, respiratory regulation involves a wakeful (voluntary) drive modulated by behavioural 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 non-rapid 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 apnoea 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 apnoea threshold while transitioning from awake to asleep, a central apnoea may occur. Once the apnoea threshold is reached, ventilation resumes. The ventilatory control set point is determined by hydrogen ion concentration in the cerebrospinal fluid in contact with the ventral medullary surface, the anatomical location of the central chemoreceptors.[2][19]​ These transitional central apnoeas at sleep onset are common in healthy individuals, and are distinct from the recurrent pathological central apnoeas that occur during sleep.

CSA syndromes are sub-divided into hypercapnic and non-hypercapnic forms. Hypercapnic breathing disorders are characterised by reduced respiratory drive, or reduced neuromuscular activity (e.g., neuromuscular diseases). In non-hypercapnic forms of central apnoea, 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., non-hypercapnic 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 apnoeic threshold. When CO₂ drops below the apnoeic threshold, a CSA event (undershoot) will occur and last until the CO₂ increases above the threshold. Therefore, PaCO₂ levels oscillate above and below the apnoeic threshold and cause the typical cyclic hyperventilation, followed by central apnoea 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 apnoeas and/or hypopnoeas (cessation and/or reduction of ventilation without respiratory effort) during sleep, resulting in somnolence or hypersomnia, in a person without a known medical or neurological disorder.

CSA with Cheyne-Stokes breathing (CSB)

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

CSA due to high-altitude periodic breathing

  • Periods of central apnoeas and/or hypopnoeas alternating with periods of hyperpnoea occurring during sleep, typically after ascending to altitudes of around 8000 feet (2500 metres) or above, although it is also described at lower altitudes (4900 feet [around 1500 metres]).[3]

CSA due to medical condition without CSB

  • Central apnoeas without characteristics of CSB occurring in people with an underlying medical or neurological condition such as vascular, neoplastic, degenerative, demyelinating, or traumatic injury to the brainstem. Thought to be relatively rare (with the possible exception of post-stroke central apnoea).

CSA due to medication or substance misuse

  • Central apnoeas in the form of ataxic breathing (variable length of CSAs and respiration rate) or intermittent and sporadic central apnoeas, 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 apnoeas or hypopnoeas) and emergence or persistence of central apnoea or central hypopnoea.

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