Impaired pharyngeal reflex responses to negative pressure: a novel cause of sleep apnea in multiple sclerosis.

Obstructive sleep apnea (OSA) is common in people with multiple sclerosis (MS). However, people with MS often do not have "typical" anatomical risk factors (i.e., nonobese and female predominance). Accordingly, nonanatomical factors such as impaired upper-airway muscle function may be particularly important for OSA pathogenesis in MS. Therefore, this study aimed to investigate genioglossus (largest upper-airway dilator muscle) reflex responses to brief pulses of upper-airway negative pressure in people with OSA and MS. Eleven people with MS and OSA and 10 OSA controls without MS matched for age, sex, and OSA severity were fitted with a nasal mask, pneumotachograph, choanal and epiglottic pressure sensors, and intramuscular electrodes into genioglossus. Approximately 60 brief (250 ms) negative pressure pulses (approximately -12 cmH2O mask pressure) were delivered every 2-6 breaths at random during quiet nasal breathing during wakefulness to determine genioglossus electromyogram (EMGgg) reflex responses (timing, amplitude, and morphology). Where available, recent clinical MRI brain scans were evaluated for the number, size, and location of brainstem lesions in the group with MS. When present, genioglossus reflex excitation responses were similar between MS participants and controls (e.g., peak excitation amplitude = 229 ± 85% vs. 282 ± 98% baseline, P = 0.17). However, ∼30% of people with MS had either an abnormal (predominantly inhibition) or no protective excitation reflex. Participants with MS without a reflex had multiple brainstem lesions including in the hypoglossal motor nucleus which may impair sensory processing and/or efferent output. Impaired pharyngeal reflex function may be an important contributor to OSA pathogenesis for a proportion of people with MS.NEW & NOTEWORTHY This study investigated the function of an important reflex that helps protect the upper airway from closing during negative (suction) pressure in people with and without multiple sclerosis (MS) and obstructive sleep apnea (OSA). We found that ∼30% of people with MS had either no protective reflex or an abnormal reflex response. These findings indicate that impaired upper-airway reflex function may be an important contributor to OSA for a substantial proportion of people with MS.

Sleep-Disordered Breathing in People with Multiple Sclerosis: Prevalence, Pathophysiological Mechanisms, and Disease Consequences.

Sleep problems are common in people with multiple sclerosis (MS). Reported prevalence rates of sleep-disordered breathing (SDB) vary between 0 and 87%. Differences in recruitment procedures and study designs likely contribute to the wide variance in reported prevalence rates of SBD in MS. This can make attempts to compare SDB rates in people with MS to the general population challenging. Little is known about the pathophysiological mechanisms that contribute to SDB in people with MS or whether MS contributes to SDB disease progression. However, compared to the general obstructive sleep apnea (OSA) population, there are clear differences in the clinical phenotypes of SDB in the MS population. For instance they are typically not obese and rates of SDB are often comparable or higher to the general population, despite the high female predominance of MS. Thus, the risk factors and pathophysiological causes of SDB in people with MS are likely to be different compared to people with OSA who do not have MS. There may be important bidirectional relationships between SDB and MS. Demyelinating lesions of MS in the brain stem and spinal cord could influence breathing control and upper airway muscle activity to cause SDB. Intermittent hypoxia caused by apneas during the night can increase oxidative stress and may worsen neurodegeneration in people with MS. In addition, inflammation and changes in cytokine levels may play a key role in the relationship between SDB and MS and their shared consequences. Indeed, fatigue, neurocognitive dysfunction, and depression may worsen considerably if both disorders coexist. Recent studies indicate that treatment of SDB in people with MS with conventional first-line therapy, continuous positive airway pressure therapy, can reduce fatigue and cognitive impairment. However, if the causes of SDB differ in people with MS, so too may the optimal therapy. Thus, many questions remain concerning the relationship between these two disorders and the underlying mechanisms and shared consequences. Improved understanding of these factors has the potential to unlock new therapeutic targets.

Mechanisms contributing to the response of upper-airway muscles to changes in airway pressure.

This study assessed the effects of inhaled lignocaine to reduce upper airway surface mechanoreceptor activity on 1) basal genioglossus and tensor palatini EMG, 2) genioglossus reflex responses to large pulses (∼10 cmH2O) of negative airway pressure, and 3) upper airway collapsibility in 15 awake individuals. Genioglossus and tensor palatini muscle EMG and airway pressures were recorded during quiet nasal breathing and during brief pulses (250 ms) of negative upper-airway pressure. Lignocaine reduced peak inspiratory (5.6 ± 1.5 vs. 3.8 ± 1.1% maximum; mean ± SE, P < 0.01) and tonic (2.8 ± 0.8 vs. 2.1 ± 0.7% maximum; P < 0.05) genioglossus EMG during quiet breathing but had no effect on tensor palatini EMG (5.0 ± 0.8 vs. 5.0 ± 0.5% maximum; P = 0.97). Genioglossus reflex excitation to negative pressure pulses decreased after anesthesia (60.9 ± 20.7 vs. 23.6 ± 5.2 µV; P < 0.05), but not when expressed as a percentage of the immediate prestimulus baseline. Reflex excitation was closely related to the change in baseline EMG following lignocaine (r(2) = 0.98). A short-latency genioglossus reflex to rapid increases from negative to atmospheric pressure was also observed. The upper airway collapsibility index (%difference) between nadir choanal and epiglottic pressure increased after lignocaine (17.8 ± 3.7 vs. 28.8 ± 7.5%; P < 0.05). These findings indicate that surface receptors modulate genioglossus but not tensor palatini activity during quiet breathing. However, removal of input from surface mechanoreceptors has minimal effect on genioglossus reflex responses to large (∼10 cmH2O), sudden changes in airway pressure. Changes in pressure rather than negative pressure per se can elicit genioglossus reflex responses. These findings challenge previous views and have important implications for upper airway muscle control.