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Con: Sleep Apnea Is Not an Anatomic Disorder

Center for Sleep Disorders Research, Louis Stokes Cleveland DVA Medical Center, Case Western Reserve University, Cleveland, Ohio

The most fundamental argument for neural events as initiating obstructive sleep apnea is the fact that closure of the pharyngeal airway occurs during sleep. In sleep, there is a reorganization of cortical (e.g., neural) control that includes changes in direct cortical drive to and peripheral reflex control of the muscles of the chest wall and upper airway and ventilation (1). The disease-defining event is state-related, requiring sleep in the presentation of the disease-obstructive sleep apnea–hypopnea syndrome (2, 3). The presence of an anatomic encroachment of the upper airway by itself does not produce an obstruction. Obesity, tonsillar hypertrophy, neuromuscular disease, and a craniopharyngeal anomaly are risk factors present during wakefulness but do not invariably produce obstructive sleep apnea (4). Apparent anatomic predispositions require greater levels of upper airway muscle activity to maintain an open airway during wakefulness. With sleep onset, however, this neural compensation is reduced (1), thus providing the fundamental cause.

In the original analysis (5) as well as in peer-reviewed published records by others, electromyographic recordings of patients with obstructive sleep apnea consistently inform me that respiratory muscle activity declines before and with the onset of the first obstructive breath. (The main limitation of using these studies is that they are contaminated with state changes. Increased upper airway muscle activity with arousal as well as the "startle"-like effect that Horner talks about could create an illusion that upper airway activity is decreased and that that is why apnea occurs. The timing data, however, are more compelling. Upper airway activity begins before pump muscles. This is observed not only in the genioglossus muscle but also in other muscles of the upper airway, including the alae nasi, a muscle loaded by intrapharyngeal events (6). Even if phasic activity is observed, preceding the obstruction or early in the obstructive event there is a reduction or reversal in the interval between the onset of activation of pharyngeal muscles and either the onset of inspiratory flow or chest wall muscle activation (6). In contrast, those individuals without sleep apnea exhibit a consistent ( 100–200 milliseconds) interval of preactivation before the events of inspiration, an interval that is more apparent at sleep onset and with sleep than during wakefulness (7). Furthermore, individuals with evidence of inspiratory flow limitation (individuals without apnea who snore) are dependent on their ventilatory motor output to preserve upper airway patency during sleep. In such individuals, mild hypoxia (8) or mild hypocapnia (9) is needed to precipitate occlusion—findings that indicate the critical role of respiratory control in the determination of sleep apnea. Therefore, for one obstructive apnea to occur there is an attenuation of neuromuscular activation in both amount and coordination that permits the airway to close. Once closed, other neural events, such as motor coordination (5, 6), inertia in the control system (10), and/or arousal from sleep, determine apnea length. The main point is that to close a nasopharynx during sleep a deactivation of neuromuscular drive is required, and then to reopen the air passage another set of neural events acts to determine duration and recovery of the obstruction.

One apnea is not enough. Obstructive sleep apnea–hypopnea syndrome is characterized by many obstructive events of a given length (greater than 10 seconds in the adult). The repetitive waxing and waning of ventilation in obstructive sleep apnea–hypopnea syndrome is initiated and sustained by a respiratory control (e.g., neural) system (11). Short-term potentiation of ventilation, or ventilatory after-discharge, is a phenomenon that can be evoked by brief hypoxia exposure, promotes ventilatory stability, and protects against dysrhythmic breathing (12). An absence of short-term potentiation is reported for patients with obstructive sleep apnea–hypopnea syndrome (13) or for patients with congestive heart failure who have recurrent central sleep apnea—Cheyne–Stokes respiration (14). Finally, central and obstructive apneas may occur in the same patient over a night indicating that the neural tendency to cycle is the fundamental event (15, 16) and that upper airway obstruction is not essential for the development of recurrent neural apneas.

Periodic breathing is subject to fundamental analysis. Sleep, increased time delay, and decreased damping of the system are known to promote respiratory instability through "loop gain" (11, 12). Mathematical models predict a correlation between the incidence of periodic breathing and hypoxic sensitivity (17); indeed, Cheyne–Stokes respiration (periodic breathing) during sleep occurs more frequently in those with congestive heart failure and higher peripheral chemosensitivity (18). In the case of obstructive sleep apnea, added effects of reflex responses to airway occlusion and/or the arousal needed to open an occluded airway serve to create an "overshoot" in ventilatory drive and make it more likely to cycle (17). Hence, neural factors produce and can either amplify or attenuate the probability of having the repetitive events that lead to sleep apnea syndrome.

In summary, obstructive sleep apnea is precipitated and maintained by neural events. Our focus should be on optimizing neural drive to muscles that maintain upper airway patency during sleep and on preventing the next apnea though stabilization of respiratory control. In essence, the therapeutic goal is to keep the airway awake and let the brain sleep.

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