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

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 during REM sleep [12, 14].

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.

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 OSA [15].

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

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

inflammation [2].

respiration.

**2. Pathophysiology**

chemoreceptors is also reduced during sleep [1].

sporadic, though a minority of patients have familial disease. Numerous abnormalities exist in cellular and molecular function in ALS, including protein aggregation, mitochondrial dysfunction, DNA and RNA processing and central nervous system

The hallmark of clinical disease is the presence of both upper and lower motor neuron signs. Weakness in ALS starts as asymmetrical or focal, and then progresses to generalized weakness, ultimately affecting all skeletal muscles. Loss of motor neurons in the brainstem and spinal cord causes weakness of the pharyngeal, laryngeal, intercostal and diaphragmatic muscles. This predisposes patients with ALS to respiratory dysfunction (the physiology behind this to be detailed below). When respiratory dysfunction becomes severe, tracheostomy and permanent ventilation are required. From the time of the diagnosis the median survival time is 3 to 5 years.

There are two FDA approved medications for ALS. Riluzole was approved in 1997 and provides a modest survival benefit of 3 months. A second medication, Edaravone, a free radical scavenger, was approved in 2017, but is only approved for use in ALS patients without respiratory insufficiency, and is controversial for clinical use due to its burdensome administration schedule and questionable clinical efficacy [5]. Numerous clinical drug trials have failed to demonstrate marked clinical benefit in ALS. However, provision of non-invasive ventilation has shown survival benefit in some ALS patients [6]. The dearth of effective treatment options for ALS underscores the importance of modifying those factors that optimize quality of life and extension of survival, particularly sleep and

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

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

The most common cause of death in ALS is respiratory failure [3, 4].

**52**

obstructive sleep apnea [1].

breathing [11]. Therefore, when OSA is suspected a polysomnogram should be requested to confirm its diagnosis.

In regard to the effects of sleep-disordered breathing on quality of life, ALS patients often complain of excessive daytime sleepiness resulting from nocturnal sleep fragmentation and insomnia. Nocturnal hypoventilation results in orthopnea, morning headaches, excessive daytime sleepiness, and cognitive dysfunction [12, 17]. A study showed the most common nocturnal complaints in ALS patients were nocturia, sleep fragmentation, and cramps (each seen in about half of the patients) [19]. **Table 1** shows the common sleep disturbances seen in ALS.

Nocturnal restlessness, sleep fragmentation with multiple awakening, snoring, and apneas leads to excessive daytime sleepiness, difficulties to arouse in the morning, difficulties to arouse from sleep, cognitive problems and poor work performance. In severe cases when insomnia and sleep continuity is severely impaired patients develop lethargy, cyanosis, early morning headaches, nausea and vomiting and leg edema. **Table 2** shows the most common sleep features in ALS patients.

Patients with ALS suffer from other conditions that also affect the sleep such as restless leg syndrome (RLS), REM-sleep behavior disorder (RBD), cramps, immobility-associated discomfort, pain, depression-related sleep disorders and dementia-related sleep disorders which may affect the sleep continuity. Even patients newly diagnosed with ALS have shown poor sleep quality related to depression and poor nocturnal mobility [12, 17, 19].

There are important secondary cardiopulmonary effects of chronic nocturnal hypoxemia that should not be overlooked. These include pulmonary hypertension, right heart failure and arrhythmia. There is also an increased risk of stroke, myocardial infarction and lethal cardiac arrhythmias. This highlights the critical

Insomnia Excessive daytime sleepiness Sleep fragmentation Sleep related hypoventilation Sleep breathing disorders

#### **Table 1.**

*Sleep disturbances in ALS.*


**55**

**Table 3.**

Arterial Blood Gas (ABG) Pulmonary Function Tests

Sniff Nasal Pressure (SNP) Overnight Pulse Oximetry Polysomnography (PSG)

• Sitting and supine forced vital capacity (FVC)

*Investigations commonly used to detect sleep disorders in amyotrophic lateral sclerosis.*

• Maximal inspiratory pressure (MIP) • Maximal expiratory pressure (MEP)

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

need to diagnose and treat sleep-disordered breathing early particular in ALS where

Essential to the identification of ALS patients with sleep abnormalities is maintaining a high index of suspicion and taking a detailed sleep history. This ideally takes place with a family member or caregiver present (or anyone who may share a bed with the patient). This second party can provide history regarding the patient's behaviors during sleep and functioning in the daytime (some of which the patient himself/herself may not be aware of). Specific questions regarding the presence of excessive daytime sleepiness, cognitive dysfunction, orthopnea, apneas and snoring are essential. Frequent awakenings, snoring and choking are clues for suspecting obstructive sleep apnea. Nocturnal orthopnea is often an early sign of respiratory dysfunction causing hypoventilation. Commonly used screening tools for sleep disorders include STOP-BANG, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index Scale [3]. All patients with respiratory dysfunction or bulbar weakness should be screened for sleep disorders. Close attention should be placed on examining for signs of respiratory dysfunction such as accessory muscle use (particularly when supine). Increased work of breathing can result in weight loss and cachexia. Patients with bulbar dysfunction progressively develop changes in their voice, dif-

ficulty clearing secretions, weak cough and difficulty swallowing [21].

laboratory investigations used to diagnose sleep disorders in ALS.

There are multiple modalities that can be utilized in the diagnostic evaluation of respiratory muscle weakness and sleep disorders in ALS. The use of more than one modality increases the precision and accuracy of the diagnosis and prevents over- or underestimation of respiratory muscle strength [20]. **Table 3** outlines the different

If hypoventilation is suspected, then spirometry should be requested. Clinical indicators include excessive daytime sleepiness, morning headaches, frequent nocturnal waking, and vivid dreams [22]. Forced vital capacity (FVC) has long been used to predict survival and disease progression in ALS patients. Faster progression of disease has been associated with FVC < 75 percent of predicted value. A more accurate measure of weakness of the diaphragm is supine FVC however this can be difficult to evaluate [21, 22]. The difference between standing and supine FVC correlates with orthopnea and a fall from sitting to supine >20 percent has a sensitivity of 90 percent for identifying diaphragmatic weakness [12], whereas sitting FVC < 50 percent has only a sensitivity of 58 percent. Despite wide availability in obtaining FVC it is not as sensitive for early respiratory dysfunction and values may be inaccurate in patients with bulbar dysfunction who cannot maintain a tight seal on the mouth piece [21].

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

lifespan is devastatingly shortened [20].

**4. Diagnosis**

**Table 2.** *Sleep-related features in ALS.* *The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep… DOI: http://dx.doi.org/10.5772/intechopen.98934*

need to diagnose and treat sleep-disordered breathing early particular in ALS where lifespan is devastatingly shortened [20].
