**2. Pathophysiology**

Adequate involuntary ventilation is essential for effective sleep. The pathway by which voluntary ventilation occurs involves the cerebral cortex, brainstem and corticospinal tracts to motor neurons in the C3-C5 spinal segments which supply the phrenic nerve. The phrenic nerve innervates the diaphragm. In the state of wakefulness (in which both voluntary and involuntary ventilation persists), the diaphragm is the major inspiratory muscle and is assisted by accessory muscles. The accessory inspiratory muscles include the intercostals, trapezius, scalenes, sternocleidomastoid and pectoralis major muscles. Involuntary or automatic breathing involves the respiratory centers in the brainstem (pons and medulla). This is the central respiratory drive. Oxygen and carbon dioxide levels sensed by chemoreceptors (peripheral and central) directly influence automatic breathing (which is then carried out through the spinal segments formerly mentioned innervating the diaphragm through the phrenic nerve). During non-REM sleep, muscle tone is decreased and during REM sleep muscle tone is almost completely lost. Automatic ventilation during sleep is almost completely dependent on the diaphragm (particularly in REM sleep) therefore diaphragmatic dysfunction (such as that seen in ALS) can predispose to hypoventilation and nocturnal hypoxemia. The sensitivity of chemoreceptors is also reduced during sleep [1].

Effective sleep also depends on maintaining a patent upper airway. Patency of the upper airway is dependent on secondary muscles of respiration, which include the muscles of the pharynx. Pharyngeal muscle tone is maintained by trigeminal sensory afferents during inspiration, when negative pressure is generated. This prevents upper airway collapse. Weakness of pharyngeal muscles (such as in ALS) leaves one susceptible to airway collapse and the upper airway resistance seen in obstructive sleep apnea [1].

**53**

OSA [15].

*The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep…*

**3. Clinical features of sleep disturbances in amyotrophic lateral sclerosis**

Sleep disorders are quite prevalent in patients with ALS, but often underreported, misdiagnosed, and undertreated. It has been shown that the onset of nocturnal breathing abnormalities often precedes the onset of overt daytime respiratory dysfunction [3]. A recent study showed that sleep disorders occur in 70 percent of patients with ALS, where 65 percent have insomnia, 50 percent have sleep-breathing disorders including hypoventilation, and 85 percent suffer from

The most common form of sleep disturbance encountered in ALS is due to hypoventilation, rather than obstructive nocturnal events [8]. As ALS progresses, the involvement of the respiratory muscles is unavoidable; this results in nocturnal hypoventilation [9, 10]. Hypoventilation is the primary etiology of nocturnal oxygen desaturation (hypoxemia) in patients with ALS. This is due to bilateral phrenic nerve dysfunction resulting in diaphragmatic weakness or paralysis [11]. Nocturnal hypoventilation is first present when supine, as this is where the diaphragm is put at its worst mechanical disadvantage resulting in a drop in lung volumes [3, 12]. Diaphragmatic dysfunction in ALS is of particular concern in regard to sleep-disordered breathing as the diaphragm is the sole active respiratory muscle during REM sleep (where accessory and intercostal muscles are naturally inhibited) [13]. For this reason, nocturnal hypoventilation is especially worse

Quality of sleep in those without advanced disease can be normal (although quality of life is impacted by respiratory muscle weakness) [11]. As the disease progresses fragmentation of stage N3 of sleep occurs due to loss of circadian rhythms [13]. All stages of sleep are eventually affected resulting in daytime hypercapnia which is defined as an elevated CO2 > 45 mm Hg. Hypoxemia and hypercapnia result from respiratory failure and the hypoventilation syndrome caused by restrictive thoracic disease from weakness of respiratory muscles. This hypoventilation syndrome results in a decrease in sensitivity of chemoreceptors due to chronic hypercapnia [15]. Hypoventilation is further complicated with the co-existence of

Sleep-breathing disorders are common in ALS. Oropharyngeal weakness affecting dilatory muscles leads to obstructive sleep apnea that presents like in non-ALS OSA patients with snoring, snorting, apneas, and frequent nocturnal arousals [16]. In a study of 18 patients with ALS, it was found on polysomnography that total sleep time was decreased, and frequency of sleep-disordered breathing and arousals were higher than in age-matched controls. Eight of these patients were found to have periods of hypoventilation (most often during REM sleep). There were no recorded apneas. Bulbar involvement did not show a significant association with degree of sleep-disordered breathing [2]. Bulbar weakness does however predispose to obstructive sleep apnea due to weakness of tongue protrusion and palatal control. Bulbar weakness is also associated with increased secretions and weak cough [13]. That being said, since patients with bulbar ALS have tongue atrophy, they have less prevalence of OSA [17, 18]. Central sleep apneas in ALS patients may result from central motor neuron impairment, though they are less frequent than

Particular importance should be placed on addressing respiratory muscle weakness (hypoventilation) rather than the number of apneas or hypopneas on polysomnography in ALS patients [11]. OSA is common in ALS and if untreated shortens the survival of ALS patients [3, 12]. Non-invasive positive pressure ventilation can prolong time to tracheostomy and provide benefit in regard to quality of life in the setting of respiratory muscle weakness and sleep-disordered

*DOI: http://dx.doi.org/10.5772/intechopen.98934*

night-time awakening related to ALS symptoms [7].

during REM sleep [12, 14].

sleep-breathing disorders.

*The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep… DOI: http://dx.doi.org/10.5772/intechopen.98934*
