Central Sleep Apnoea

CSA is broadly divided into two categories based on aetiology

• Primary (Idiopathic) CSA: This rare form occurs without any identifiable underlying cause. Diagnosis requires the exclusion of other medical, neurological, or substance-related contributors.
• Secondary CSA: More commonly encountered in clinical practice, secondary CSA arises due to an identifiable condition or external factor. The most frequent associations include:
  • Congestive heart failure (both preserved and reduced ejection fraction), where CSA often coexists with Cheyne-Stokes breathing (CSB), a distinctive crescendo-decrescendo respiratory pattern.
  • Cerebrovascular accidents, especially those affecting the brainstem.
  • Chronic opioid use, which suppresses the respiratory rhythm via μ-opioid receptor activation in the medulla.
  • Renal failure, particularly in patients on dialysis.
  • High-altitude exposure, leading to periodic breathing triggered by hypobaric hypoxia.

CSA can also be classified physiologically

• Hyperventilation-Related CSA: This includes primary CSA, CSA associated with heart failure, high-altitude CSA, and treatment-emergent CSA. These forms are characterised by unstable ventilatory control mechanisms, typically manifesting with periods of ventilatory overshoot (hyperventilation) followed by hypocapnia, which triggers central apnoeas.
• Hypoventilation-Related CSA: Less commonly, CSA may arise from global hypoventilation syndromes. These typically occur when there is inadequate respiratory drive or muscular capacity, such as in neuromuscular disorders, structural chest wall abnormalities (e.g., kyphoscoliosis), or central nervous system pathology that blunts the arousal response.

Primary (Idiopathic) CSA

• By definition, idiopathic CSA is diagnosed when no identifiable cause can be determined despite thorough evaluation.
• It is a rare condition, constituting a minority of CSA cases.
• Typically presents in middle-aged to older males without comorbid conditions or exposure to contributing substances.

Secondary CSA

Cheyne-Stokes Breathing (CSB)–Associated CSA

• Most commonly linked with congestive heart failure (CHF), particularly with reduced left ventricular ejection fraction.
• Also associated with stroke and end-stage renal disease.
• Characterised by a crescendo-decrescendo breathing pattern interspersed with central apnoeas or hypopnoeas.
• Daytime hypocapnia (PaCO₂ <38 mmHg) and comorbid atrial fibrillation increase susceptibility.

CSA Due to Medical Conditions Without CSB

• Attributable to structural or functional disruption of central respiratory control, including:
  • Brainstem lesions (vascular, neoplastic, traumatic, demyelinating, or degenerative)
  • Neurological diseases (e.g., multiple system atrophy, mitochondrial disorders)
  • Spinal cord injuries, especially low cervical tetraplegia
  • Endocrinopathies such as acromegaly and hypothyroidism

CSA Associated with Medications or Substances

• Chronic opioid use (including methadone therapy) is a well-established cause due to μ-opioid receptor-mediated suppression of the brainstem respiratory rhythm generator.
• Benzodiazepines, antidepressants, and gabapentinoids may contribute through blunting arousal responses or CNS depression.
• Non-opioid agents such as baclofen, sodium oxybate, valproate, and gabapentin may cause CSA via GABAergic inhibition of respiratory centres.
• Ticagrelor, a P2Y₁₂ antagonist, has been rarely implicated, potentially through activation of pulmonary C-fibre reflexes.

CSA Due to High-Altitude Periodic Breathing

• Occurs in otherwise healthy individuals exposed to hypobaric hypoxia at elevations typically above 2500–4000 metres.
• Hypoxaemia-induced hyperventilation may cause PaCO₂ to fall below the apnoeic threshold, triggering central apnoeas during NREM sleep.
• Manifestations are usually self-limited upon descent or acclimatisation.

Predisposing Risk Factors

Age

• Prevalence increases markedly in individuals over 65.
• Age-related factors include reduced ventilatory responsiveness and increased likelihood of underlying cardiopulmonary or neurological disease.

Sex

• CSA is significantly more common in males.
• Testosterone is thought to elevate the apnoeic threshold during sleep, while oestrogen may offer a protective effect via enhanced carbon dioxide reserve.

Cardiac Disorders

• Heart failure (both preserved and reduced EF) and atrial fibrillation are strongly associated with CSA.
• CSA may act both as a consequence and a contributor to cardiac dysfunction, creating a cyclical burden.

Stroke

• Acute stroke may precipitate CSA in up to 26% of patients within 72 hours, often in the form of CSB.
• Symptoms tend to resolve in the subacute phase, suggesting transient autonomic instability.

Renal Failure

• CSA occurs in a notable proportion of haemodialysis patients.
• Uraemic effects on chemosensitivity and ventilatory instability are implicated.

Other Neurological and Endocrine Disorders

• Conditions such as acromegaly, primary mitochondrial disease, and hypothyroidism affect ventilatory control centres or respiratory mechanics.

• Central Sleep Apnoea (CSA) arises from dysregulation of the respiratory control system during sleep, particularly in the transition from wakefulness to non-rapid eye movement (NREM) sleep, where chemical stimuli dominate respiratory drive. 
• Its underlying mechanisms can be broadly divided into two primary pathophysiologic categories: ventilatory instability and depression of the central respiratory control centres. 
• These processes interact with sleep stage transitions, chemoreceptor feedback loops, and neuromechanical factors to produce the episodic respiratory failure seen in CSA.

Normal Ventilatory Control and Sleep Transition

• Wakefulness: Breathing is regulated by both behavioural (voluntary) and chemical (PaCO₂, PaO₂) influences, with cortical control allowing modulation in response to speech, emotion, and posture.
• NREM Sleep: Behavioural input fades; respiratory drive is governed primarily by metabolic control via central (medullary) and peripheral (carotid body) chemoreceptors.
• REM Sleep: Ventilatory control becomes more irregular due to pontine modulation, creating vulnerability to transient apnoeic events.
• PaCO₂ Apnoeic Threshold: During sleep, the apnoeic threshold is set slightly above wakeful PaCO₂ levels. Minor reductions in PaCO₂—often 2–5 mmHg—below this threshold can inhibit central respiratory output and provoke apnoea.

Ventilatory Instability and Loop Gain

Loop Gain Components

• Controller Gain: Reflects chemoreceptor sensitivity (i.e. how strongly ventilation changes in response to fluctuations in PaCO₂).
• Plant Gain: Represents how much a given change in ventilation alters PaCO₂ (influenced by lung volume, dead space, and metabolic rate).
• Circulatory Delay: The lag between changes in blood gas levels and their detection by central or peripheral chemoreceptors.

High Loop Gain

• Causes overcompensation for small disturbances in PaCO₂.
• Leads to hyperventilation (overshoot) → PaCO₂ falls below the apnoeic threshold → central apnoea (undershoot).
• Results in periodic breathing patterns such as Cheyne-Stokes respiration.

Contributing Factors to High Loop Gain

• Heart failure (prolonged circulatory delay and heightened chemosensitivity).
• High altitude (hypoxia-induced hyperventilation).
• Stroke and renal failure (altered chemoreflexes).

Central Respiratory Depression Syndromes

Narcotics/Opioids

• Act on μ-opioid receptors in the medulla and peripheral chemoreceptors, reducing sensitivity to hypercapnia and hypoxia.
• Long-term opioid use results in blunted ventilatory responses, particularly during sleep when behavioural drive is absent.
• May induce irregular (Biot) breathing patterns or sustained hypoventilation.

Brainstem Disorders

• Tumours, infarctions, trauma, or infections involving the medulla can disrupt the respiratory rhythm generator.
• Patterns may include Biot respiration—clusters of breaths alternating with apnoea without a regular periodic pattern.

Sleep Stage–Dependent Features

Sleep Onset Transitional Apnoeas

• Common in healthy individuals; typically resolve as stable sleep is achieved.
• Occur when PaCO₂ falls below the elevated apnoeic threshold during early NREM sleep.

NREM Dominance of CSA

• Most pathological central apnoeas occur during NREM, where chemical control predominates.
• REM-related CSA is rarer and less understood, but likely influenced by pontine excitatory/inhibitory inputs to the medullary centres.

Role of Upper Airway Patency

• Although CSA is characterised by absent respiratory effort, upper airway behaviour remains relevant
• During central apnoeas, the pharyngeal airway may become narrowed or closed.
• If both diaphragmatic and pharyngeal dilator muscle activity cease, mixed apnoea may result.
• If airway patency is preserved, the apnoea remains purely central
• This overlap is evident when obstructive apnoeas convert to Cheyne-Stokes patterns during CPAP therapy, due to ventilatory overshoot from improved airway patency.

General Population

• Prevalence: CSA affects less than 1% of the general adult population.
• In a large community-based polysomnographic study of 5804 adults aged ≥40 years, the overall prevalence was 0.9%, with approximately half of these cases showing features of Cheyne-Stokes breathing (CSB).
• The median age of affected individuals was 69 years.
• CSA was significantly more common in men (1.8%) than women (0.2%).

Subtypes and Associated Conditions

Cheyne-Stokes Breathing–CSA (CSB-CSA)

• Occurs predominantly in patients with congestive heart failure (CHF), particularly those with reduced ejection fraction.
• Estimated prevalence in CHF patients ranges from 25% to 40%, depending on disease severity, left ventricular function, and coexistent arrhythmias such as atrial fibrillation.

Post-Stroke CSA

• Prevalence varies widely, with estimates ranging from 1.4% to 19%.
• CSA is particularly observed in the acute phase post-stroke and may resolve with neurological recovery.

Opioid-Induced CSA

• Up to 30% of patients on chronic opioid therapy, including those in methadone maintenance programmes, exhibit CSA features.
• Respiratory instability arises due to opioid-induced depression of medullary respiratory centres and peripheral chemoreceptors.

High-Altitude CSA

• High-altitude periodic breathing is common in healthy individuals exposed to elevations above 4000 metres (13,000 feet).
• It is more prevalent in men and occurs at lower altitudes in susceptible individuals.

Chronic Kidney Disease (CKD)

• CSA has been reported in up to 10% of patients with CKD, especially those undergoing dialysis.
• Likely related to fluid overload, uremia-induced chemoreceptor instability, and autonomic dysfunction.

Primary (Idiopathic) CSA

• A rare form comprising approximately 4% of diagnosed CSA cases.
• Primarily affects middle-aged to older adults, with a male predominance.

Neurological Disorders

• Precise prevalence is uncertain, but CSA is reported in various central and neuromuscular conditions:
  • Multiple system atrophy
  • Amyotrophic lateral sclerosis (ALS)
  • Multiple sclerosis
  • Neuromuscular diseases affecting respiratory mechanics

Demographic Risk Factors

Age

• Prevalence increases with age.
• A cross-sectional study in men aged ≥65 years reported a prevalence of 2.7% using a modified ICSD-3 diagnostic framework.
• Older individuals exhibit heightened chemosensitivity and diminished ventilatory stability during NREM sleep, predisposing to CSA.

Sex

• CSA, particularly CSB-CSA, is significantly more prevalent in men.
• Women, especially premenopausal, are relatively protected, likely due to hormonal modulation of the apnoeic threshold.
• Men typically have a lower threshold for PaCO₂-induced apnoea, making them more susceptible to ventilatory instability.

Race

• Currently, there is no robust data available regarding racial or ethnic variation in CSA prevalence.

General Symptoms of Sleep Disruption

• Excessive Daytime Sleepiness (EDS): Frequently reported, though often less severe than in OSA. Some patients may not recognise sleepiness, especially those with chronic heart failure, possibly due to heightened sympathetic tone masking fatigue.
• Nonrestorative Sleep: Described as waking unrefreshed despite adequate sleep duration.
• Sleep Fragmentation: Recurrent nocturnal awakenings, often unprovoked, suggest disrupted sleep architecture.
• Difficulty Initiating or Maintaining Sleep (Insomnia): Particularly sleep-maintenance insomnia is common in CSA, especially among males (79% in CSA vs. 49% in OSA).
• Morning Headaches: May be due to overnight hypercapnia or intermittent nocturnal hypoxia.
• Fatigue and Poor Concentration: Secondary to fragmented sleep and oxygen desaturation.
• Transient Nocturnal Dyspnoea: Awakening with sudden shortness of breath, often linked to the ventilatory overshoot after an apnoea.
• Paroxysmal Nocturnal Dyspnoea: Especially in CSA related to Cheyne-Stokes breathing, can reflect underlying heart failure.
• Nocturnal Angina or Palpitations: Occur due to intermittent hypoxaemia and increased sympathetic drive.

Witnessed Symptoms (as Reported by Bed Partners)

• Apnoeic Episodes: Observed cessation of breathing during sleep.
• Periodic Breathing: Rhythmic pattern of waxing and waning respiration may be noted, particularly in Cheyne-Stokes respiration.
• Snoring: Less common than in OSA, but may still be present—especially in mixed apnoea syndromes.

Symptoms Related to Underlying Aetiology

• Cardiac Symptoms: Dyspnoea on exertion, orthopnoea, leg swelling, and fatigue may indicate heart failure.
• Neurological Symptoms: History of stroke, tremors, balance issues, or previous CNS infections should raise concern for central nervous system contributions.
• Renal Symptoms: Uraemic features in dialysis patients or those with known CKD.
• Substance Use History: Chronic opioid use, including methadone or heroin, is a critical historical point.
• Endocrine Disorders:
  • Acromegaly: Associated with increased CSA prevalence due to altered ventilatory control.
  • Hypothyroidism: May be a contributing factor, though the mechanism remains unclear. 

 Polysomnography (PSG)

• Gold standard diagnostic test for CSA.
• Conducted in a specialised sleep laboratory with overnight monitoring.
• Measures multiple parameters:
  • Sleep stages: via EEG, EOG, and submental EMG.
  • Respiratory effort: via thoracic and abdominal bands.
  • Airflow: via nasal pressure transducer and oronasal thermistor.
  • Oxygen saturation: via continuous pulse oximetry.
  • Cardiac rhythm: via ECG.
• Video and audio recording used to monitor patient behaviour and movement during sleep.
• Key diagnostic features on PSG:
  • ≥5 central apnoeas and/or hypopnoeas per hour of sleep.
  • Central events comprise >50% of total respiratory events.
  • Apnoeas must be ≥10 seconds with no respiratory effort.
  • Predominantly seen in NREM sleep and in supine position.
• Characteristic breathing patterns:
  • Cheyne-Stokes: ≥3 central events with crescendo-decrescendo amplitude and cycle ≥40 seconds.
  • Ataxic breathing: Irregular rate, depth, and duration of breaths.
  • High-altitude periodic breathing: Cyclical central apnoeas with cycle length 12–34 seconds.
• Limitations:
  • Home sleep tests are not suitable for CSA due to inability to detect respiratory effort.
  • If sleep quality is inadequate, PSG may need to be repeated with sleep aids.

Diagnostic Criteria (ICSD-3)

Primary CSA

• PSG confirms ≥5 central events/hour.
• Central events >50% of total.
• No Cheyne-Stokes pattern.
• At least one symptom (e.g., insomnia, non-restorative sleep, witnessed apnoeas).
• No alternative explanation (e.g., hypoventilation, medications, other disorders).

CSA with Cheyne-Stokes breathing

• PSG as above with clear Cheyne-Stokes pattern (crescendo-decrescendo amplitude, cycle ≥40 seconds).
• Associated with heart failure, atrial fibrillation, or neurological disease.

CSA due to high altitude

• Occurs at altitudes ≥2500 m.
• PSG (or clinical observation) reveals ≥5 central events/hour.
• Patient reports disturbed sleep, morning headache, or witnessed breathing abnormalities.
• No better explanation by another disorder or drug.

CSA due to medication/substance

• History of opioid or respiratory depressant use.
• PSG shows ≥5 central events/hour, with >50% being central.
• No alternative cause identified.

Additional Investigations to Identify Underlying Aetiologies

Thyroid Stimulating Hormone (TSH)

• Indicated if symptoms suggest hypothyroidism (e.g., cold intolerance, dry skin, constipation).
• Elevated in primary hypothyroidism; follow up with T3 and T4 if abnormal.

Serum Creatinine

• Performed if unexplained oedema or suspicion of renal dysfunction.
• Elevated levels suggest chronic kidney disease, which can contribute to CSA.

Electrocardiogram (ECG)

• Recommended in all patients where heart failure or atrial fibrillation is suspected.
• May reveal arrhythmias, ischaemia, or left ventricular hypertrophy.

Echocardiography

• Essential in patients with signs of heart failure.
• Assesses systolic and diastolic function, valvular disease, and pulmonary pressures.
• LVEF ≤45% is a contraindication to adaptive servo-ventilation therapy.

Serum Insulin-Like Growth Factor 1 (IGF-1)

• Ordered when acromegaly is suspected based on clinical features.
• Elevated IGF-1 levels may suggest a growth hormone–secreting pituitary adenoma contributing to CSA.

Neuroimaging (Brain MRI or CT)

• Considered if neurological symptoms are present (e.g., cranial nerve deficits, hemiparesis).
• Identifies structural lesions (e.g., infarcts, tumours, demyelination, Chiari malformation).

Diagnostic Considerations and Limitations

• CSA rarely occurs in isolation; most patients also exhibit obstructive apnoeas, especially with increasing obesity.
• Classification inconsistencies in research studies make it difficult to apply uniform criteria.
• Hypopnoea subtyping is inconsistently reported across laboratories; many classify all hypopnoeas as obstructive, potentially missing central hypopnoeas.
• Premenopausal women may have central hypopnoeas that are misclassified, leading to underdiagnosis.
• PSG should ideally be done after optimisation of comorbidities like heart failure, as CSA severity correlates with cardiac status.

Obstructive Sleep Apnoea (OSA)

• Most commonly confused with CSA due to overlapping symptoms, including nocturnal awakenings, excessive daytime sleepiness, and episodic hypoxaemia.
• Distinguished by the presence of respiratory effort during apnoeas, caused by upper airway collapse.
• Snoring, obesity, and observed apnoeas with gasping or choking are more characteristic of OSA.
• PSG shows chest and abdominal movements during events, unlike the absent effort in CSA.

Periodic Limb Movements of Sleep (PLMS)

• Characterised by repetitive involuntary movements of the limbs, especially the lower extremities, during sleep.
• Often associated with arousals that lead to sleep fragmentation and non-restorative sleep.
• Can result in daytime fatigue and insomnia.
• PSG reveals stereotyped limb jerks with EMG bursts, unrelated to respiratory effort or airflow changes.

Narcolepsy

• Presents primarily with profound daytime sleepiness and sudden sleep attacks.
• May include cataplexy (sudden muscle weakness), hypnagogic hallucinations, and sleep paralysis.
• Sleep-onset REM periods on multiple sleep latency testing support the diagnosis.
• Not typically associated with cyclic desaturation or disrupted nocturnal breathing as seen in CSA.

Shift Work Sleep Disorder

• Common among rotating or night-shift workers due to circadian rhythm disruption.
• Chronic sleep deprivation leads to daytime fatigue and poor concentration.
• Sleep episodes are often delayed or fragmented due to social and work obligations.
• No abnormal breathing patterns observed on PSG; symptoms resolve with sleep schedule normalisation.

Chronic Obstructive and Restrictive Lung Diseases

• Include conditions such as COPD, interstitial lung disease, and thoracic cage abnormalities.
• Patients experience nocturnal hypoventilation, particularly in REM sleep, with resultant oxygen desaturation and arousals.
• PSG may reveal shallow breathing and prolonged hypoxaemia without the central cessation of effort seen in CSA.
• Associated symptoms include exertional dyspnoea and chronic cough.

Neuromuscular Disorders

• Diseases such as amyotrophic lateral sclerosis (ALS) or muscular dystrophies affect ventilatory mechanics.
• Respiratory failure worsens during sleep, especially REM, due to reduced accessory muscle tone.
• PSG findings include hypoventilation and desaturations with preserved effort, distinguishing them from true central apnoeas.
• Examination may reveal generalised weakness, fasciculations, or areflexia.

Poorly Controlled Asthma

• Nocturnal bronchospasm leads to arousals, cough, and episodic dyspnoea.
• Symptoms are typically worse in the early morning hours.
• PSG may show increased arousals but normal breathing effort and preserved airflow in the absence of obstruction.
• Daytime spirometry and history of variability in peak flow support the diagnosis.

 General Principles

• The primary goals of CSA management are to normalise breathing during sleep, improve sleep quality, and reduce daytime symptoms such as fatigue and somnolence.
• Therapy should address both the CSA itself and any associated or underlying conditions (e.g., heart failure, opioid use, CNS disorders).
• Patients with significant daytime somnolence or impaired function should be cautioned against driving or operating machinery.

Approach by Subtype

 Primary (Idiopathic) CSA

• Initial treatment typically involves a trial of continuous positive airway pressure (CPAP).
• Adaptive servo-ventilation (ASV) may be more consistently effective than CPAP, but guidelines often require failure of CPAP before ASV is tried.
• If positive airway pressure fails, pharmacological options include acetazolamide or sedative-hypnotics (e.g., zolpidem, triazolam), though evidence is limited and use must be individualised.

CSA with Cheyne-Stokes Breathing (CSB) in Heart Failure

• Begin by optimising heart failure management using guideline-directed medical therapy (e.g., beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists).
• CPAP can reduce the apnoea-hypopnoea index (AHI), improve oxygenation, and may benefit cardiac function.
• ASV is contraindicated in heart failure with reduced ejection fraction (LVEF ≤45%) due to increased cardiovascular mortality risk.
• Supplemental nocturnal oxygen (2–5 L/min via nasal cannula) can improve saturation and reduce AHI, but impact on long-term outcomes is uncertain.
• Bilevel positive airway pressure (BPAP) with a backup rate may be an option in selected patients, although long-term outcome data are lacking.
• Cardiac resynchronisation therapy may reduce CSA severity in selected heart failure patients.

CSA Due to High Altitude

• Descent to lower altitude is the most effective intervention.
• Supplemental oxygen improves symptoms and sleep-related desaturation.
• Acetazolamide enhances ventilatory response and improves sleep-disordered breathing; may be used alone or with CPAP in OSA patients at altitude.

CSA Secondary to Medications/Substance Use

• First-line strategy is dose reduction or discontinuation of offending agents (e.g., opioids, sedatives).
• Positive airway pressure therapy (CPAP or ASV) may be beneficial if symptoms persist.
• BPAP with a backup rate is considered in cases of suspected opioid-induced hypoventilation.
• Evidence regarding response to ASV is mixed.

Treatment-Emergent CSA

• Emergent CSA following initiation of CPAP for obstructive sleep apnoea often resolves over time.
• Persistent cases may require non-invasive ventilation; ASV has shown better control of respiratory events than CPAP in this context.
• ASV is particularly effective in improving AHI, REM sleep, and arousal index in patients without underlying heart failure.

Hypoventilation-Related CSA

• Occurs in conditions such as neuromuscular diseases, central nervous system pathology, or severe pulmonary mechanics abnormalities.
• First-line treatment is BPAP (with or without backup rate); a backup rate is advisable if patient effort is insufficient.
• Acetazolamide can be considered to stimulate respiration via mild metabolic acidosis.

Other Therapies

Pharmacologic

• Acetazolamide: Reduces central events by stimulating respiration through induced acidosis.
• Limited evidence; should be used cautiously and monitored for side effects.

Implantable Devices

• Phrenic nerve stimulation (e.g., remedē System) delivers diaphragmatic stimulation via an implantable device.
• Useful in symptomatic CSA patients who fail or cannot tolerate CPAP or other non-invasive therapies.
• Evidence suggests sustained improvement in AHI and quality of life up to 36 months, but further research is needed. 

 General Prognostic Understanding

• Long-term prognosis data for CSA are limited, particularly for idiopathic or secondary CSA not associated with heart failure. 
• Most outcome data focus on CSA associated with Cheyne-Stokes breathing (CSB) in patients with congestive heart failure (CHF), which has been consistently associated with adverse clinical outcomes.

CSA with Cheyne-Stokes Breathing in Heart Failure

• CSA-CSB is an independent predictor of mortality and cardiac transplantation in patients with CHF.
• Pathophysiological mechanisms contributing to poor outcomes include repetitive nocturnal apnoeic episodes that provoke sympathetic nervous system activation, promoting arrhythmias and cardiovascular strain.
• Continuous positive airway pressure (CPAP) can improve surrogate markers such as sleep quality, nocturnal oxygenation, and left ventricular ejection fraction (LVEF), but has not demonstrated a survival benefit.
• Adaptive servo-ventilation (ASV), previously considered for CSA-CSB, has been associated with increased all-cause and cardiovascular mortality in patients with CHF and reduced LVEF. Despite improving AHI and oxygenation, ASV failed to enhance quality of life or clinical outcomes in key trials.

Heart Failure Subtypes and Prognostic Variability

• Patients with preserved ejection fraction (HFpEF) and CSA may exhibit different prognostic profiles. Some studies suggest that ASV may be more beneficial in this subgroup, though evidence remains limited and inconclusive.
• The degree of CSA severity and comorbid obstructive events also appear to influence prognosis, though studies often lack sufficient power to analyse subtypes distinctly.

Need for Further Evidence

• Prognosis remains unclear for patients with idiopathic CSA, CSA due to opioid use, or CSA at high altitude. Longitudinal studies assessing mortality, hospitalisation rates, and symptom burden in these groups are lacking.
• There is an unmet need for randomised controlled trials assessing both short- and long-term effects of CSA treatment modalities—especially non-CPAP options—in broader patient cohorts. 

 Cardiovascular Morbidity and Mortality

• CSA, particularly with Cheyne-Stokes breathing (CSB), is independently associated with increased morbidity and mortality in patients with congestive heart failure (CHF).
• The cyclical nature of CSA-CSB leads to intermittent hypoxaemia and sympathetic nervous system activation, contributing to myocardial stress, arrhythmias, and cardiac remodelling.
• While continuous positive airway pressure (CPAP) improves nocturnal oxygen saturation, sleep architecture, and left ventricular ejection fraction (LVEF), it has not demonstrated a survival benefit in these patients.
• Adaptive servo-ventilation (ASV), despite reducing apnoea-hypopnoea index (AHI), has been associated with increased cardiovascular and all-cause mortality in patients with CHF and reduced LVEF.
• Longitudinal studies are needed to determine whether the mortality risk varies according to baseline cardiac function, presence of implantable defibrillators, or degree of CSA severity.

Arrhythmias

• CSA is associated with a significantly increased risk of atrial fibrillation (AF), particularly in older patients.
• The apnoeic-hyperpnoeic cycle of CSA triggers variations in autonomic tone, promoting arrhythmogenesis. During the hyperpnoeic phase, heightened chemo-stimulation, blood pressure spikes, and increased heart rate may predispose to ventricular ectopy and other arrhythmias.
• CSA may also be a predictor of sleep-specific ventricular tachycardia, especially in heart failure patients.
• Studies exploring this association often lack clear differentiation between obstructive and central apnoea subtypes, limiting definitive conclusions on causality.

Respiratory Complications

• Chronic CSA may contribute to persistent hypoventilation and lead to chronic respiratory failure, especially in individuals with underlying neuromuscular disorders or central hypoventilatory syndromes.
• Treatment-emergent CSA may paradoxically worsen with certain modalities such as bi-level positive airway pressure (BPAP), which can increase tidal volumes and exaggerate the hyperpnoea-hypocapnia cycle, thus raising the risk of central apnoeas.

Sleep Fragmentation and Neurocognitive Dysfunction

• Recurrent arousals during apnoeic episodes result in sleep fragmentation, leading to excessive daytime sleepiness, fatigue, impaired attention and memory, and mood disturbances.
• These effects may significantly impair daytime function, increase the risk of motor vehicle accidents, and reduce overall quality of life. 

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