Sleep and Sleep Disruption in Amyotrophic Lateral Sclerosis

Current Neurology and Neuroscience Reports (2020) 20: 25 https://doi.org/10.1007/s11910-020-01047-1 SLEEP (M. THORPY AND M. BILLIARD, SECTION EDITORS) Sleep and Sleep Disruption in Amyotrophic Lateral Sclerosis Matthias Boentert 1,2 Published online: 27 May 2020 # The Author(s) 2020 Abstract Purpose of Review In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge on causes, pathophysiology, and treatment of sleep disturbances in ALS. Recent Findings Motor neuron degeneration and muscle weakness may lead to muscle cramps, pain, spasticity, immobilization, restless legs, sleep-disordered breathing, and difficulties to clear secretions. Furthermore, existential fears and depression may promote insomnia. Sleep-disordered breathing, and nocturnal hypoventilation in particular, requires ventilatory support which meaningfully prolongs survival and improves health-related quality of life albeit respiratory failure is inevitable. Early indication for non-invasive ventilation can be achieved by inclusion of capnometry in diagnostic sleep studies. Summary Sleep disruption is extremely common in ALS and may arise from different etiologies. The absence of causative therapeutic options for ALS underlines the importance of symptomatic and palliative treatment strategies that acknowledge sleeprelated complaints. Keywords Amyotrophic lateral sclerosis . Sleep . Sleep-disordered breathing . Insomnia Abbreviations ALS Amyotrophic lateral sclerosis ALS-FRS-R ALS functional rating scale (revised) FVC Forced vital capacity MIP Maximum inspiratory pressure NIV Non-invasive ventilation OSA Obstructive sleep apnea PLM Periodic leg movements RBD REM sleep behavioral disorder REM Rapid eye movement RLS Restless legs syndrome SNIP Sniff nasal inspiratory pressure This article is part of the Topical Collection on Sleep * Matthias Boentert 1 Department of Neurology with Institute of Translational Neurology, University Hospital Münster (UKM), Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany 2 Department of Medicine, UKM Marienhospital Steinfurt, Steinfurt, Germany Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons. Consecutively, both spasticity and hyperreflexia may coexist with fasciculations and muscle atrophy, the latter resulting in skeletal muscle weakness virtually affecting all muscle groups. In bulbar-onset ALS, dysarthria and dysphagia usually predominate throughout the disease course. Spinal-onset subtypes of ALS arise from progressive loss of anterior horn cells which supply trunk and limb muscles [1, 2••]. Prevalence of ALS ranges from 5 to 8 per 100,000, and disease onset peaks between 50 and 70 years of age [3–6]. Lifetime risk for ALS has been reported to be 1:400 for women and 1:300 for men [7, 8]. Much is known about the molecular pathology of ALS and the genetic background of familial ALS subtypes [9] but no causative therapies have been developed to date. Only two compounds have been approved, including riluzole [10–12] and edavarone [13, 14], which both show disease-modifying effects but do not stop disease progression. Thus, muscle weakness is still inevitable and eventually leads to tetraplegia, dysarthria, swallowing dysfunction, and chronic hypercapnic respiratory failure [9, 15••]. Median survival has been reported to be 2.5–3.5 years after symptom onset and 1.5–2.5 years 25 Page 2 of 8 following diagnosis [16–18]. Chronic respiratory failure and its sequelae limit life span most and are the major cause of premature death in patients with ALS [19, 20]. ALS severely impacts activities of daily life and health-related quality of life for both patients and caregivers [21–24]. Since causative therapies are unavailable, symptom control is the hallmark of treatment, and a systematic approach to distinct disease aspects is recommended [15••]. Reduction of sleep quality substantially contributes to physical and mental health in patients with ALS [25–30]. Subsequently, sleep disturbances further increase the individual burden of disease. This review article aims to systematically outline sleep characteristics, sleep-related symptoms, and causes of sleep disruption in patients with ALS. Furthermore, it will focus not only on respiratory muscle weakness leading to sleep-related hypoventilation and chronic hypercapnic respiratory failure, but will also discuss “non-fatal” conditions which may also disrupt sleep and considerably impair health-related quality of life. Motor Symptoms of ALS and Sleep Virtually, all motor symptoms of ALS may directly affect sleep quality, including fasciculations, muscle cramps, immobilization, and even restless legs syndrome (RLS). Furthermore, impaired swallowing function, if present, puts patients at risk of sialorrhea, recurrent choking, and aspiration of saliva. Muscle fasciculations have been reported to cause sleep disturbances in some patients with ALS [31]. In addition, recurrent muscle cramps may occur, mainly affecting lower limb muscles and often exacerbating during the night. The International Classification of Sleep Disorders (ICSD-3 [32]) refers to nocturnal leg muscle cramps which are often painful, or inconvenient at least, and have been reported in patients with spinalonset ALS, in particular [28, 33]. Electrophysiologically, muscle cramps reflect spontaneous discharges of motor units at a much higher frequency (> 300 Hz) than with voluntary contraction [34]. Active stretching may help ending these discharges but may be hampered in patients in whom significant limb weakness is present. Symptomatic treatment of leg muscle cramps includes sufficient fluid intake, correction of electrolyte imbalances and, if acceptable, cessation of any causative medications. Mexiletine 150 mg twice daily has recently been reported to alleviate ALS-related muscle cramps in a randomized controlled trial [35]. Baclofen and other compounds did not show significant effects on muscle cramps in patients with ALS [36]. Quinidine (200–300 mg once to twice daily) has been evaluated in numerous other neurological conditions, showing reduction of both cramp frequency and intensity [37] but long- Curr Neurol Neurosci Rep (2020) 20: 25 term use may be associated with severe thrombocytopenia, cinchonism, and myocardial toxicity [38]. As motor function gets worse, patients may have difficulties to change position in bed. Systematic studies on this issue are lacking, but its potential to severely impair sleep quality is obvious [29]. Furthermore, immobilization renders patients more dependent on caregivers whose intervention is frequently needed for both pain relief and prevention of skin lesions [39, 40]. Diagnostic criteria for RLS include an urge to move the legs (with unpleasant or painful sensations in the lower limbs), symptom on (...truncated)