A critical analysis of the purported role of hypoxaemia in the comorbidity of obstructive sleep apnoea and epilepsy

Abstract

Obstructive sleep apnoea (OSA) is a globally prevalent sleep disorder of significant health concern and confounded with several comorbidities resulting in adverse effect(s) on quality of life in patients afflicted with it. Of particular interest is the enigmatic high comorbidity of OSA with epilepsy, the exact underlying pathophysiology of which remains elusive despite a multitude of research performed in the last four decades. Hypoxaemia, which is an important characteristic feature found in OSA during apnoeic spells, has been implicated in the high comorbidity of OSA with epilepsy, the basis of which rests upon hypoxaemia‐mediated brain damage, subcortical release phenomenon, oxidative stress and neuroinflammatory reactions. However, several studies present contradictory evidences that potentially refute the hypoxaemia‐based mechanism. Additionally, the role of hypercapnia thatgenerally accompanies hypoxaemia during apnoeic spells, cannot be overlooked and is known to be potentially protective against neuronal hyperexcitability. Thus, hypoxaemia theory implicated in the high comorbidity of OSA and epilepsy appears weak and refutable. This brief paper studies and critically analyses the role of hypoxaemia in conjunction with hypercapnia in the underlying pathophysiology of the comorbidity.

Association of patent foramen ovale with epilepsy: A hospital‐based case–control study

“…Hypoxia can enhance neuronal excitotoxicity and seizure susceptibility by increasing the level of central oxidative stress and neuroinflammation, activating microglia, and promoting the release of proinflammatory mediators and excitatory neurotransmitters 16–18 . In addition, hypoxemia‐induced reactive oxygen species and hypoxia‐inducible factor‐1 alpha could upregulate P‐glycoprotein, which is involved in drug‐resistant epilepsy, 19–21 explaining our result that PFO is an independent risk factor for drug‐resistant epilepsy. Moreover, hypoxemia could mediate CSD in the brain, holding another important role in repetitive seizures 22 …”

“…release of proinflammatory mediators and excitatory neurotransmitters. [16][17][18] In addition, hypoxemia-induced reactive oxygen species and hypoxia-inducible factor-1 alpha could upregulate P-glycoprotein, which is involved in drug-resistant epilepsy, [19][20][21] explaining our result that PFO is an independent risk factor for drug-resistant epilepsy. Moreover, hypoxemia could mediate CSD in the brain, holding another important role in repetitive seizures.…”

Relationship between right‐to‐left shunt, hypoxia, and epilepsy

“…Moreover, reactive oxygen species (ROS) induced by hypoxia are also associated with the development of DRE, probably by upregulating P‐glycoprotein 34 . Low blood oxygen levels could also cause a reduction in thalamic and hypothalamic volume, which contributes to the development of epilepsy, refractory epilepsy, and even sudden unexpected death in epilepsy 43,44 . PaO 2 is one of the most sensitive parameters of hypoxia 45 .…”

“…34 Low blood oxygen levels could also cause a reduction in thalamic and hypothalamic volume, which contributes to the development of epilepsy, refractory epilepsy, and even sudden unexpected death in epilepsy. 43,44 PaO 2 is one of the most sensitive parameters of hypoxia. 45 PWEs with RLS showed lower PaO 2 in our study, which might explain the result that RLS is an independent risk factor for DRE.…”

Intermittent hypoxia: linkage between OSAS and epilepsy

“…Collapse of upper airway further exacerbates the severity of OSAS and lead to blood hypoxemia, hypercapnia, sleep fragmentation, enhanced respiratory effort, which subsequently result in increased risks of intermittent hypoxia during sleep (Rosenzweig et al, 2014;Xing et al, 2014;Xanthopoulos et al, 2015). Long-term intermittent hypoxia could further result in a series of changes in the body, including oxidative stress, obvious inflammation, apoptosis, and neural activation (Huang et al, 2018;Patke et al, 2020;Mishra et al, 2021). Meanwhile, increased sympathetic activity during REM sleep also results in multiple systems such as cardiovascular system and nervous systems (Mokhlesi et al, 2014;Grigg-Damberger and Foldvary-Schaefer, 2021;Lehner et al, 2022).…”