Sleep Medicine Reviews xxx (2015) 1e10
Contents lists available at ScienceDirect
Sleep Medicine Reviews journal homepage: www.elsevier.com/locate/smrv
CLINICAL REVIEW
Sleep disorders and respiratory function in amyotrophic lateral sclerosis Rebekah M. Ahmed a, *, Rowena E.A. Newcombe b, Amanda J. Piper b, c, Simon J. Lewis a, b, Brendon J. Yee b, c, Matthew C. Kiernan a, Ron R. Grunstein b, c a
Brain and Mind Research Institute and Department of Neurology Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research and NeuroSleep NHMRC Centre for Research Excellence, Australia c Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Sydney Local Health District, Australia b
a r t i c l e i n f o
s u m m a r y
Article history: Received 2 February 2015 Received in revised form 7 May 2015 Accepted 20 May 2015 Available online xxx
Sleep disorders in amyotrophic lateral sclerosis (ALS) present a significant challenge to the management of patients. Issues include the maintenance of adequate ventilatory status through techniques such as non-invasive ventilation, which has the ability to modulate survival and improve patient quality of life. Here, a multidisciplinary approach to the management of these disorders is reviewed, from concepts about the underlying neurobiological basis, through to current management approaches and future directions for research. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Amyotrophic lateral sclerosis Sleep Respiratory Ventilation
Introduction Nearly all ALS patients develop respiratory symptoms at some point during their illness [1], and in a small percentage of patients respiratory failure may be the primary presentation. Respiratory insufficiency is the commonest cause of death, such that respiratory function forms a critically important prognostic indicator [2]. Progressive respiratory symptoms may also affect cognition in ALS [3], which is of further relevance to those ALS patients who develop frontotemporal dementia (FTD), a condition that shares a common pathology TDP-43 protein deposition, present in the majority of ALS patients, and in up to 50% of cases of FTD [4]. Regardless of initial presentation, respiratory symptoms across this spectrum of disorders typically develop in the context of progressive limb weakness and bulbar dysfunction. Furthermore, there is an increasing awareness that sleep symptoms including nocturnal
Abbreviations: ALS, amyotrophic lateral sclerosis; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea; SDB, sleep disordered breathing. * Corresponding author. ForeFront, Brain and Mind Research Institute, University of Sydney, 94 Mallett St Camperdown, NSW 2050, Australia. Tel.: þ61 2 9114 4250; fax: þ61 2 9114 4254. E-mail address: [email protected] (R.M. Ahmed).
hypoventilation, and hypoxia, occur independently of respiratory dysfunction, meaning that a thorough understanding of both sleep and respiratory symptoms, and the neural pathways potentially involved is imperative in the management of patients with ALS. Here we review the clinical features of respiratory dysfunction and sleep in ALS, with reference to the underlying pathophysiology and how to investigate and treat these symptoms. Respiratory function in ALS Pathophysiology of respiratory symptoms The pathophysiology of respiratory symptoms in ALS is complex and involves an interaction between multiple factors including lower and upper motor neurons, cortical structures, brainstem structures and bulbar function, many of which have not been fully elucidated. Patients not only have weakness and atrophy of limb muscles (Fig. 1), but also respiratory muscles. The process of ventilation (Fig. 2) is achieved by inspiratory and expiratory airflow with the aid of respiratory muscles. Inspiration is achieved by contraction of the diaphragm and external intercostal muscles and expiration by passive recoil of the lungs and actively generated by contraction of the rectus abdominis and internal intercostal
http://dx.doi.org/10.1016/j.smrv.2015.05.007 1087-0792/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
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R.M. Ahmed et al. / Sleep Medicine Reviews xxx (2015) 1e10
Central respiratory drive originates in the brainstem (medulla oblongata) but in the process of volitional inspiration there is also involvement of cortical areas including the supplementary motor area and pre- and primary motor areas [5e7]. Recent functional MRI studies have shown that the process of sniffing and inspiration involves activation of primary sensorimotor cortex, lateral premotor cortex, supplementary motor area, anterior cingulate, insula, basal ganglia, thalami, mesencephalon, upper pons, cerebellar vermis, piriform cortex, entorhinal cortex and parahippocampal gyrus [5]. In ALS differentiating the involvement of both peripheral and central dysfunction in disordered breathing is difficult. There is evidence of both respiratory muscle weakness [8] and diaphragmatic EMG evidence that lower motor neuron involvement is prominent. However there is also evidence of upper motor neuron involvement in respiratory function using transcranial magnetic stimulation [9]. Furthermore, evidence from sleep studies indicate possible prominent upper motor neuron involvement with central dysregulation and marked hypoventilation, as opposed to sleep disordered breathing (SDB) that results purely from diaphragmatic weakness. In a study involving a small cohort of ALS patients, hypoventilation, a state of severe or prolonged desaturation or combined hypercapnoea, was observed in both rapid eye movement (REM) and non REM sleep in patients with preserved diaphragmatic function, indicating likely cortical involvement [10]. Clinical symptoms of respiratory dysfunction in ALS (Table 1) Fig. 1. Image showing pattern of muscle atrophy typical of ALS. Classical limb findings in amyotrophic lateral sclerosis, with atrophy of the first dorsal interossei (shown with white arrows), “known as split hand”. Also associated atrophy involving thoracic and intercostal muscles.
muscles. The diaphragm and external intercostal muscles are innervated by lower motor neurons in the ventral horn of the spinal cord C3- C5 and T1- T12 through the phrenic and intercostal nerves. The internal intercostal and rectus abdominis muscles are innervated by motor neurons located in segments T1-T12 and L1 to L5 of the spinal cord.
Often the signs of respiratory dysfunction are subtle and easily overlooked, but commonly include sleep disturbance, morning inertia or awaking unrefreshed, with headache and excessive daytime somnolence, and significant cognitive change and dysfunction. Specific questions and examination are often required to detect early respiratory failure. More obvious signs of respiratory dysfunction include reduced exercise tolerance, dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea [11]. As symptoms progress and patients develop bulbar symptoms they can exhibit changes in their voice (volume and tone), difficulty
Fig. 2. Structures involved in control of ventilation. Inspiration and expiration is controlled by different segments of the ventral spinal cord. Respiration also requires input from the brainstem and cortical structures. In ALS disordered breathing is likely the result of muscle weakness secondary to degeneration involving the motor neurons in the spinal cord, but also central factors involving the brainstem and cortex.
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
R.M. Ahmed et al. / Sleep Medicine Reviews xxx (2015) 1e10 Table 1 Respiratory signs and symptoms in ALS. Symptoms of respiratory dysfunction Reduced exercise tolerance Dyspnea on exertion Orthopnea Cognitive change and dysfunction Paroxysmal nocturnal dyspnea Symptoms related to bulbar dysfunction - change in voice character - increased secretions - poor cough - difficulty swallowing Examination findings Use of accessory muscles of breathing Increased work of breathing at rest Weight loss Pooling of secretions
in clearing secretions, poor cough and swallowing difficulties [12]. Recurrent aspirations can further impair respiratory function. Patients presenting to clinic should be closely examined for subtle signs of respiratory failure including use of accessory muscle of breathing, particularly when supine as an indicator of respiratory compromise [13]. ALS patients tend to lose weight as the disease progresses. This cachectic process may in part relate to the increased work of breathing and may be so severe as to require nutritional support via enteral feeding [14]. Factors that can modify respiratory function Increasingly it is being recognized that metabolism may affect respiratory function in ALS. Patients with ALS may manifest a state of hypermetabolism particularly around the time of diagnosis [15e17], the mechanism of which remains to be elucidated, but it is likely that changes in metabolic rate and energy stores may affect both ventilatory drive and respiratory muscle function. Adding further weight to this hypothesis is the finding that blood lipid levels are decreased in ALS patients with lower forced vital capacity (FVC) values [18] and that lipid levels may correlate with disease progression and survival [19]. Percutaneous endoscopic gastrostomy (PEG) is offered to many patients with ALS with bulbar involvement and in an effort to help maintain nutrition and prevent weight loss [20]. Evidence of an overall benefit on survival is limited, however timing of insertion needs to be considered closely with the suggestion that complication rates from PEG tube insertion may increase with decreasing respiratory function, with an FVC 80cmH2O or MEP >90cmH2O performed correctly rules out clinically important inspiratory or expiratory muscle weakness [24]. Sniff nasal and transdiaphragmatic pressures More recent studies have used sniff nasal pressure (SNP) and transdiaphragmatic sniff pressure as a measure of respiratory muscle strength in ALS. SNP is a volitional test of inspiratory and diaphragmatic strength, whilst transdiaphragmatic sniff pressure is a non-volitional measure of strength after bilateral cervical magnetic stimulation of the phrenic nerves [25]. SNP is a non-invasive test and has been found to have a strong predictive value of muscle strength [8]. It has also been used to monitor disease progression and can be correlated with nocturnal hypoxia and prognosis [23]. Arterial blood gases In addition to nocturnal oxygen saturation monitoring and capnigraphy, the gold standard to measure the adequacy of ventilation is an early morning arterial blood gas to measure oxygen and carbon dioxide levels [11] to better reflect nocturnal blood gases [26]. An elevated bicarbonate and low serum chloride level have been correlated with respiratory symptoms that are predictive of death [1]. Sleep disorders in ALS Sleep disorders are a common and can be an early manifestation of ALS, but may go undetected until the later stages of disease. Abnormal breathing during sleep is frequently present and may occur even in patients with normal respiratory function and no signs of diaphragmatic denervation [10,27]. Various studies have reported obstructive and central apneas as well as non-obstructive hypoventilation in patients with ALS [28,29]. Other factors can also produce sleep disturbance, including restless legs syndrome, depression and anxiety, pain, difficulty changing position due to muscle weakness, excessive secretions and increased myoclonic activity disturbing sleep.
Investigation of respiratory function Nocturnal hypoxia and hypoventilation Pulmonary function tests Forced vital capacity is historically the most commonly used respiratory measurement in ALS and is a well recognised predictor of survival [22]. FVC values of less than 75% of predicted baseline values have also been associated with faster disease progression [22]. Supine FVC, whilst more difficult to perform is a more accurate measure of diaphragmatic weakness than erect FVC [1], and the differences between erect and supine FVC have been correlated with orthopnea [13]. Whilst FVC is widely available it has a number
Changes in breathing during sleep commonly precede awake respiratory symptoms and can be fatal. The development of abnormal breathing and gas exchange during sleep is influenced by the distribution and extent of respiratory and upper airway muscle weakness, and is often concurrent with phrenic denervation and secondary diaphragmatic weakness. SDB including mixed apnea/hypopnea states can occur in the absence of diaphgramatic weakness, though the prevalence of SDB in ALS is yet to be determined [10]. When apneas are present,
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
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R.M. Ahmed et al. / Sleep Medicine Reviews xxx (2015) 1e10
studies have reported these events to be predominantly central in nature [28,29], although obstructive events associated with nocturnal hypoxaemia can also occur, especially in the setting of upper airway muscle weakness [28]. Continuous positive airway pressure ventilation (CPAP) can be used for obstructive sleep apnoea [30] but controlled studies are lacking. NIV involving bilevel ventilation is currently the mainstay of therapy due to better tolerability and is discussed in the NIV section. The incidence of hypoventilation in this population is high. In a prospective observational study of 38 ambulatory patients with ALS followed over a 26 month period from first presentation to an ALS clinic, over two thirds developed signs of hypoventilation [1]. Hypoventilation typically worsens during REM sleep as this is the period of sleep in which postural muscle inhibition normally occurs resulting in a critical dependence on diaphragmatic contraction to maintain adequate ventilation. In the presence of diaphragmatic dysfunction and loss of persisting phasic muscle tone of the extradiaphragmatic muscles such as the sternocleidomastoids, significant hypoventilation and oxygen desaturation can occur [31]. A high index of clinical suspicion regarding the presence of REM hypoventilation is important, as the onset of diaphragmatic weakness may not always lead to orthopnea, but instead a subclinical worsening in the recumbent position detectable only with investigational studies. Restless legs syndrome An association is present between ALS and restless legs syndrome (RLS) particularly in those older than 64 years [32], with one cohort study of 69 patients with ALS finding 18 patients (13.8%) to have RLS according to International RLS Study Group criteria [33]. Restless legs syndrome entails an unpleasant sensory disturbance affecting sleep initiation associated with ‘creeping’ or aching in the lower limbs, relieved by movement [34]. Though a distinct syndrome, RLS is almost certainly varied in terms of aetiology, with increased risk due to iron deficiency [35], genetic predisposition [36] and peripheral neuropathy among other causes [37]. An overlap with periodic limb movements of sleep (PLMS) or involuntary, repetitive and regular limb movements independent of apnea, have been identified [38,39]. Whilst RLS is associated with sleep disturbance in ALS, the pathophysiology and treatment remains largely unstudied. Mood disorders Mood disturbance is closely related to sleep disorder and is a prominent feature in ALS that is often of pathological severity and found more commonly in FTD variants [40]. Mood disturbance may occur as a phenomenon of adjustment to medical illness, a primary psychological disorder, a manifestation of the underlying etiology of ALS with limbic involvement, a side effect of medication or may relate to a period of diagnostic uncertainty and thereby delay [41]. Features of apathy and depression are also extremely common, particularly in the context of cognitive dysfunction, occurring in up to 80% and 30% of patients respectively [40]. This is suggested to have a greater impact on care giver burden, than motor features [42]. Anxiety is common in ALS and associated with impaired sleep quality and insomnia disorders. Anxiety may be severe enough enough to affect the uptake of non-invasive ventilation (NIV) [43]. Cicardian disturbances Many patients with ALS complain of disturbed sleep, daytime sleepiness and fatigue. Whilst this undoubtedly is contributed to by respiratory issues and muscle fatigue, it is possible that there is a
disturbance of cicardian rhythms independent of these factors. Circadian rhythms are controlled by centres in the thalami and hypothalamus [44] and there is increasing evidence of thalamic [44,45] and hypothalamic involvement in ALS and other neurodegenerative conditions [46,47]. Interestingly, a mouse model of ALS mice has been reported to have an aberrant serum corticosterone circadian rhythm which correlated with earlier paralysis [48]. Other factors disturbing sleep The impact of motor symptoms on sleep should not be underestimated. Symptoms include immobility and nocturnal cramps [49] which are often refractory to treatment [50]. Discomfort may also arise from excess saliva and cough, which may be ameliorated in some patients by NIV [51]. Effect of sleep on cognition There is a well-recognised literature describing the bidirectional relationships between sleep and cognition in a number of neurodegenerative conditions including Alzheimer's and Parkinson's disease [52,53]. The relationship between cognition and sleep in ALS is not well understood, however it is clear that cognitive disturbance in ALS is important for its negative impact on prognosis [54]. The severity and extent of cognitive decline in ALS varies widely from mild cognitive dysfunction to marked cognitive impairment and dementia [55,56]. Severe changes are best recognized within the FTD form of ALS with an onset typically during the sixth decade. The C9orf72 repeat expansion accounts for over a third of known genetically determined ALS and provides a genetic link between FTD and ALS. This mutation has been associated with earlier disease onset, worsened cognition and behavior, early psychiatric disturbance and poorer survival [57,58]. It is possible that chronic hypoventilation with secondary hypoxia, hypercapnia, metabolic or inflammatory abnormalities contribute to cognitive decline in ALS. One study found an association between recurrent nocturnal de-oxygenation/re-oxygenation, and memory retention or retrieval [3]. Early research suggested that such impairment may be reversible and 1 small case series of ALS patients with ventilatory disturbance and age-matched controls found that subsequent treatment with NIV resulted in partial benefit on cognition. The memory domain was predominantly affected, with 2 out of 7 cognitive tests pertaining to visual and verbal memory and learning significantly improving with this therapy [59]. Importantly, NIV patients in this study all had evidence of daytime hypercapnia (>49 mmHg) however, hypersomnolence was somewhat narrowly defined as an Epworth sleepiness scale > 10 and the severity was undetermined. In the same study, performance on the story recall test, which involves an attentional component showed no differences, perhaps indicating that attentional impairment related to hypersomnolence was not a factor, and that primary cerebral changes related to hypoventilation may be in play. Investigation of sleep symptoms Nocturnal oximetry While oximetry may be used to detect both intermittent and sustained nocturnal hypoxemia, during both REM and NREM sleep [60], it does not provide any information about sleep quality or architecture. Not only is REM sleep the period of greatest vulnerability for developing nocturnal hypoventilation, a marked reduction of REM sleep duration has been shown to be associated with reduced survival in ALS [31]. Since a significant number of patients
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
R.M. Ahmed et al. / Sleep Medicine Reviews xxx (2015) 1e10
with ALS fail to achieve REM sleep during diagnostic investigations [60], oximetry alone could underestimate the severity of respiratory compromise. Furthermore, oximetry measures oxygen saturation only and not hypoventilation per se. Polysomnography Polysomnography (PSG) provides a more detailed assessment of the respiratory and non-respiratory factors contributing to nonspecific complaints of poor or unrefreshing sleep, and is useful in providing prognostic information in this patient group [61]. However, while attended PSG is a valuable tool for distinguishing the underlying cause of reported sleep disturbances, it can also be a difficult undertaking for non-ambulant patients with high care needs. Resources for attended PSG are also limited in some settings. Unattended diagnostic PSG recording in the patient's home is one potential alternative. Split night PSG studies (diagnostic and treatment) within a single night are widely used in the management of patients with simple obstructive sleep apnea. However, this approach is frequently inconclusive for adequately assessing nocturnal hypoventilation and completing titration of non-invasive ventilation in patients with ALS due to poor sleep efficiency and the absence of REM sleep [62]. Whether sleep disordered breathing is investigated using oximetry, PSG or polygraphy in a sleep laboratory or in the patients' home, simultaneous monitoring of transcutaneous or end-tidal carbon dioxide should be undertaken to better detect sleep hypoventilation [63]. Treatment of sleep and respiratory symptoms Whilst there is currently no cure for ALS, the clinical focus remains on measures to prolong survival and improve patient quality of life. Management of sleep and respiratory symptoms is central to this. Pharmacological Many neuroprotective strategies have been explored in ALS, with a dearth of successful agents identified, especially in humans by comparison with experimental evidence [64]. Riluzole, a glutamate and excitatory regulator thought to stimulate glutamate uptake, has demonstrated a partial benefit on survival in the order of 3 months (Class 1 evidence) [65,66], with benefits accentuated by use of a specialized multidisciplinary setting [67]. It has also been shown that Riluzole has some properties for the treatment of experimental hypoxia-induced gasping [68] and duration of REM/ NREM sleep [69]. Nocturnal ventilation and non-invasive ventilation In a small number of ALS cases, OSA is the predominant form of SDB, which may respond to CPAP at least initially. However many patients find single level pressure difficult to tolerate, particularly when diaphragmatic and abdominal muscle weakness becomes more advanced. Consequently, non-invasive positive pressure ventilation (NIV) remains the mainstay of respiratory treatment for patients with ALS [70e72]. Bilevel ventilation devices are most commonly used as initial therapy (see below). Using NIV, improvements in symptoms, quality of life and survival are achievable [73e75], although these benefits are primarily limited to those with normal to moderate bulbar weakness [76]. While patients with severe bulbar dysfunction are less likely to tolerate [77,78] or benefit from NIV [76,79] relief of sleep-related symptoms may still occur [76]. Therefore, the available evidence is in favour of offering NIV to all patients with ALS, including those with poor bulbar function [75].
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When to introduce non-invasive ventilation The most appropriate time to introduce NIV in ALS has not been determined. In the only randomized trial to date, criteria for commencing NIV were either orthopnea with MIP < 60% predicted or symptomatic daytime hypercapnia (PaCO2 >45 mmHg). However, an earlier study found that patients with orthopnea but without daytime hypercapnia or nocturnal desaturation responded to NIV in a similar fashion. In addition, when the more rigid criteria for initiating therapy were used in a randomized trial, 6 of the 19 patients allocated to standard care died within the first 2 weeks of the study [76], suggesting advanced and unstable respiratory compromise was already present by the time symptoms and moderate alterations in lung function were identified. Current recommendations for considering a trial of NIV include any of the following: PaCO2 >45 mmHg, MIP
Contents lists available at ScienceDirect
Sleep Medicine Reviews journal homepage: www.elsevier.com/locate/smrv
CLINICAL REVIEW
Sleep disorders and respiratory function in amyotrophic lateral sclerosis Rebekah M. Ahmed a, *, Rowena E.A. Newcombe b, Amanda J. Piper b, c, Simon J. Lewis a, b, Brendon J. Yee b, c, Matthew C. Kiernan a, Ron R. Grunstein b, c a
Brain and Mind Research Institute and Department of Neurology Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research and NeuroSleep NHMRC Centre for Research Excellence, Australia c Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Sydney Local Health District, Australia b
a r t i c l e i n f o
s u m m a r y
Article history: Received 2 February 2015 Received in revised form 7 May 2015 Accepted 20 May 2015 Available online xxx
Sleep disorders in amyotrophic lateral sclerosis (ALS) present a significant challenge to the management of patients. Issues include the maintenance of adequate ventilatory status through techniques such as non-invasive ventilation, which has the ability to modulate survival and improve patient quality of life. Here, a multidisciplinary approach to the management of these disorders is reviewed, from concepts about the underlying neurobiological basis, through to current management approaches and future directions for research. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Amyotrophic lateral sclerosis Sleep Respiratory Ventilation
Introduction Nearly all ALS patients develop respiratory symptoms at some point during their illness [1], and in a small percentage of patients respiratory failure may be the primary presentation. Respiratory insufficiency is the commonest cause of death, such that respiratory function forms a critically important prognostic indicator [2]. Progressive respiratory symptoms may also affect cognition in ALS [3], which is of further relevance to those ALS patients who develop frontotemporal dementia (FTD), a condition that shares a common pathology TDP-43 protein deposition, present in the majority of ALS patients, and in up to 50% of cases of FTD [4]. Regardless of initial presentation, respiratory symptoms across this spectrum of disorders typically develop in the context of progressive limb weakness and bulbar dysfunction. Furthermore, there is an increasing awareness that sleep symptoms including nocturnal
Abbreviations: ALS, amyotrophic lateral sclerosis; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea; SDB, sleep disordered breathing. * Corresponding author. ForeFront, Brain and Mind Research Institute, University of Sydney, 94 Mallett St Camperdown, NSW 2050, Australia. Tel.: þ61 2 9114 4250; fax: þ61 2 9114 4254. E-mail address: [email protected] (R.M. Ahmed).
hypoventilation, and hypoxia, occur independently of respiratory dysfunction, meaning that a thorough understanding of both sleep and respiratory symptoms, and the neural pathways potentially involved is imperative in the management of patients with ALS. Here we review the clinical features of respiratory dysfunction and sleep in ALS, with reference to the underlying pathophysiology and how to investigate and treat these symptoms. Respiratory function in ALS Pathophysiology of respiratory symptoms The pathophysiology of respiratory symptoms in ALS is complex and involves an interaction between multiple factors including lower and upper motor neurons, cortical structures, brainstem structures and bulbar function, many of which have not been fully elucidated. Patients not only have weakness and atrophy of limb muscles (Fig. 1), but also respiratory muscles. The process of ventilation (Fig. 2) is achieved by inspiratory and expiratory airflow with the aid of respiratory muscles. Inspiration is achieved by contraction of the diaphragm and external intercostal muscles and expiration by passive recoil of the lungs and actively generated by contraction of the rectus abdominis and internal intercostal
http://dx.doi.org/10.1016/j.smrv.2015.05.007 1087-0792/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
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R.M. Ahmed et al. / Sleep Medicine Reviews xxx (2015) 1e10
Central respiratory drive originates in the brainstem (medulla oblongata) but in the process of volitional inspiration there is also involvement of cortical areas including the supplementary motor area and pre- and primary motor areas [5e7]. Recent functional MRI studies have shown that the process of sniffing and inspiration involves activation of primary sensorimotor cortex, lateral premotor cortex, supplementary motor area, anterior cingulate, insula, basal ganglia, thalami, mesencephalon, upper pons, cerebellar vermis, piriform cortex, entorhinal cortex and parahippocampal gyrus [5]. In ALS differentiating the involvement of both peripheral and central dysfunction in disordered breathing is difficult. There is evidence of both respiratory muscle weakness [8] and diaphragmatic EMG evidence that lower motor neuron involvement is prominent. However there is also evidence of upper motor neuron involvement in respiratory function using transcranial magnetic stimulation [9]. Furthermore, evidence from sleep studies indicate possible prominent upper motor neuron involvement with central dysregulation and marked hypoventilation, as opposed to sleep disordered breathing (SDB) that results purely from diaphragmatic weakness. In a study involving a small cohort of ALS patients, hypoventilation, a state of severe or prolonged desaturation or combined hypercapnoea, was observed in both rapid eye movement (REM) and non REM sleep in patients with preserved diaphragmatic function, indicating likely cortical involvement [10]. Clinical symptoms of respiratory dysfunction in ALS (Table 1) Fig. 1. Image showing pattern of muscle atrophy typical of ALS. Classical limb findings in amyotrophic lateral sclerosis, with atrophy of the first dorsal interossei (shown with white arrows), “known as split hand”. Also associated atrophy involving thoracic and intercostal muscles.
muscles. The diaphragm and external intercostal muscles are innervated by lower motor neurons in the ventral horn of the spinal cord C3- C5 and T1- T12 through the phrenic and intercostal nerves. The internal intercostal and rectus abdominis muscles are innervated by motor neurons located in segments T1-T12 and L1 to L5 of the spinal cord.
Often the signs of respiratory dysfunction are subtle and easily overlooked, but commonly include sleep disturbance, morning inertia or awaking unrefreshed, with headache and excessive daytime somnolence, and significant cognitive change and dysfunction. Specific questions and examination are often required to detect early respiratory failure. More obvious signs of respiratory dysfunction include reduced exercise tolerance, dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea [11]. As symptoms progress and patients develop bulbar symptoms they can exhibit changes in their voice (volume and tone), difficulty
Fig. 2. Structures involved in control of ventilation. Inspiration and expiration is controlled by different segments of the ventral spinal cord. Respiration also requires input from the brainstem and cortical structures. In ALS disordered breathing is likely the result of muscle weakness secondary to degeneration involving the motor neurons in the spinal cord, but also central factors involving the brainstem and cortex.
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
R.M. Ahmed et al. / Sleep Medicine Reviews xxx (2015) 1e10 Table 1 Respiratory signs and symptoms in ALS. Symptoms of respiratory dysfunction Reduced exercise tolerance Dyspnea on exertion Orthopnea Cognitive change and dysfunction Paroxysmal nocturnal dyspnea Symptoms related to bulbar dysfunction - change in voice character - increased secretions - poor cough - difficulty swallowing Examination findings Use of accessory muscles of breathing Increased work of breathing at rest Weight loss Pooling of secretions
in clearing secretions, poor cough and swallowing difficulties [12]. Recurrent aspirations can further impair respiratory function. Patients presenting to clinic should be closely examined for subtle signs of respiratory failure including use of accessory muscle of breathing, particularly when supine as an indicator of respiratory compromise [13]. ALS patients tend to lose weight as the disease progresses. This cachectic process may in part relate to the increased work of breathing and may be so severe as to require nutritional support via enteral feeding [14]. Factors that can modify respiratory function Increasingly it is being recognized that metabolism may affect respiratory function in ALS. Patients with ALS may manifest a state of hypermetabolism particularly around the time of diagnosis [15e17], the mechanism of which remains to be elucidated, but it is likely that changes in metabolic rate and energy stores may affect both ventilatory drive and respiratory muscle function. Adding further weight to this hypothesis is the finding that blood lipid levels are decreased in ALS patients with lower forced vital capacity (FVC) values [18] and that lipid levels may correlate with disease progression and survival [19]. Percutaneous endoscopic gastrostomy (PEG) is offered to many patients with ALS with bulbar involvement and in an effort to help maintain nutrition and prevent weight loss [20]. Evidence of an overall benefit on survival is limited, however timing of insertion needs to be considered closely with the suggestion that complication rates from PEG tube insertion may increase with decreasing respiratory function, with an FVC 80cmH2O or MEP >90cmH2O performed correctly rules out clinically important inspiratory or expiratory muscle weakness [24]. Sniff nasal and transdiaphragmatic pressures More recent studies have used sniff nasal pressure (SNP) and transdiaphragmatic sniff pressure as a measure of respiratory muscle strength in ALS. SNP is a volitional test of inspiratory and diaphragmatic strength, whilst transdiaphragmatic sniff pressure is a non-volitional measure of strength after bilateral cervical magnetic stimulation of the phrenic nerves [25]. SNP is a non-invasive test and has been found to have a strong predictive value of muscle strength [8]. It has also been used to monitor disease progression and can be correlated with nocturnal hypoxia and prognosis [23]. Arterial blood gases In addition to nocturnal oxygen saturation monitoring and capnigraphy, the gold standard to measure the adequacy of ventilation is an early morning arterial blood gas to measure oxygen and carbon dioxide levels [11] to better reflect nocturnal blood gases [26]. An elevated bicarbonate and low serum chloride level have been correlated with respiratory symptoms that are predictive of death [1]. Sleep disorders in ALS Sleep disorders are a common and can be an early manifestation of ALS, but may go undetected until the later stages of disease. Abnormal breathing during sleep is frequently present and may occur even in patients with normal respiratory function and no signs of diaphragmatic denervation [10,27]. Various studies have reported obstructive and central apneas as well as non-obstructive hypoventilation in patients with ALS [28,29]. Other factors can also produce sleep disturbance, including restless legs syndrome, depression and anxiety, pain, difficulty changing position due to muscle weakness, excessive secretions and increased myoclonic activity disturbing sleep.
Investigation of respiratory function Nocturnal hypoxia and hypoventilation Pulmonary function tests Forced vital capacity is historically the most commonly used respiratory measurement in ALS and is a well recognised predictor of survival [22]. FVC values of less than 75% of predicted baseline values have also been associated with faster disease progression [22]. Supine FVC, whilst more difficult to perform is a more accurate measure of diaphragmatic weakness than erect FVC [1], and the differences between erect and supine FVC have been correlated with orthopnea [13]. Whilst FVC is widely available it has a number
Changes in breathing during sleep commonly precede awake respiratory symptoms and can be fatal. The development of abnormal breathing and gas exchange during sleep is influenced by the distribution and extent of respiratory and upper airway muscle weakness, and is often concurrent with phrenic denervation and secondary diaphragmatic weakness. SDB including mixed apnea/hypopnea states can occur in the absence of diaphgramatic weakness, though the prevalence of SDB in ALS is yet to be determined [10]. When apneas are present,
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
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studies have reported these events to be predominantly central in nature [28,29], although obstructive events associated with nocturnal hypoxaemia can also occur, especially in the setting of upper airway muscle weakness [28]. Continuous positive airway pressure ventilation (CPAP) can be used for obstructive sleep apnoea [30] but controlled studies are lacking. NIV involving bilevel ventilation is currently the mainstay of therapy due to better tolerability and is discussed in the NIV section. The incidence of hypoventilation in this population is high. In a prospective observational study of 38 ambulatory patients with ALS followed over a 26 month period from first presentation to an ALS clinic, over two thirds developed signs of hypoventilation [1]. Hypoventilation typically worsens during REM sleep as this is the period of sleep in which postural muscle inhibition normally occurs resulting in a critical dependence on diaphragmatic contraction to maintain adequate ventilation. In the presence of diaphragmatic dysfunction and loss of persisting phasic muscle tone of the extradiaphragmatic muscles such as the sternocleidomastoids, significant hypoventilation and oxygen desaturation can occur [31]. A high index of clinical suspicion regarding the presence of REM hypoventilation is important, as the onset of diaphragmatic weakness may not always lead to orthopnea, but instead a subclinical worsening in the recumbent position detectable only with investigational studies. Restless legs syndrome An association is present between ALS and restless legs syndrome (RLS) particularly in those older than 64 years [32], with one cohort study of 69 patients with ALS finding 18 patients (13.8%) to have RLS according to International RLS Study Group criteria [33]. Restless legs syndrome entails an unpleasant sensory disturbance affecting sleep initiation associated with ‘creeping’ or aching in the lower limbs, relieved by movement [34]. Though a distinct syndrome, RLS is almost certainly varied in terms of aetiology, with increased risk due to iron deficiency [35], genetic predisposition [36] and peripheral neuropathy among other causes [37]. An overlap with periodic limb movements of sleep (PLMS) or involuntary, repetitive and regular limb movements independent of apnea, have been identified [38,39]. Whilst RLS is associated with sleep disturbance in ALS, the pathophysiology and treatment remains largely unstudied. Mood disorders Mood disturbance is closely related to sleep disorder and is a prominent feature in ALS that is often of pathological severity and found more commonly in FTD variants [40]. Mood disturbance may occur as a phenomenon of adjustment to medical illness, a primary psychological disorder, a manifestation of the underlying etiology of ALS with limbic involvement, a side effect of medication or may relate to a period of diagnostic uncertainty and thereby delay [41]. Features of apathy and depression are also extremely common, particularly in the context of cognitive dysfunction, occurring in up to 80% and 30% of patients respectively [40]. This is suggested to have a greater impact on care giver burden, than motor features [42]. Anxiety is common in ALS and associated with impaired sleep quality and insomnia disorders. Anxiety may be severe enough enough to affect the uptake of non-invasive ventilation (NIV) [43]. Cicardian disturbances Many patients with ALS complain of disturbed sleep, daytime sleepiness and fatigue. Whilst this undoubtedly is contributed to by respiratory issues and muscle fatigue, it is possible that there is a
disturbance of cicardian rhythms independent of these factors. Circadian rhythms are controlled by centres in the thalami and hypothalamus [44] and there is increasing evidence of thalamic [44,45] and hypothalamic involvement in ALS and other neurodegenerative conditions [46,47]. Interestingly, a mouse model of ALS mice has been reported to have an aberrant serum corticosterone circadian rhythm which correlated with earlier paralysis [48]. Other factors disturbing sleep The impact of motor symptoms on sleep should not be underestimated. Symptoms include immobility and nocturnal cramps [49] which are often refractory to treatment [50]. Discomfort may also arise from excess saliva and cough, which may be ameliorated in some patients by NIV [51]. Effect of sleep on cognition There is a well-recognised literature describing the bidirectional relationships between sleep and cognition in a number of neurodegenerative conditions including Alzheimer's and Parkinson's disease [52,53]. The relationship between cognition and sleep in ALS is not well understood, however it is clear that cognitive disturbance in ALS is important for its negative impact on prognosis [54]. The severity and extent of cognitive decline in ALS varies widely from mild cognitive dysfunction to marked cognitive impairment and dementia [55,56]. Severe changes are best recognized within the FTD form of ALS with an onset typically during the sixth decade. The C9orf72 repeat expansion accounts for over a third of known genetically determined ALS and provides a genetic link between FTD and ALS. This mutation has been associated with earlier disease onset, worsened cognition and behavior, early psychiatric disturbance and poorer survival [57,58]. It is possible that chronic hypoventilation with secondary hypoxia, hypercapnia, metabolic or inflammatory abnormalities contribute to cognitive decline in ALS. One study found an association between recurrent nocturnal de-oxygenation/re-oxygenation, and memory retention or retrieval [3]. Early research suggested that such impairment may be reversible and 1 small case series of ALS patients with ventilatory disturbance and age-matched controls found that subsequent treatment with NIV resulted in partial benefit on cognition. The memory domain was predominantly affected, with 2 out of 7 cognitive tests pertaining to visual and verbal memory and learning significantly improving with this therapy [59]. Importantly, NIV patients in this study all had evidence of daytime hypercapnia (>49 mmHg) however, hypersomnolence was somewhat narrowly defined as an Epworth sleepiness scale > 10 and the severity was undetermined. In the same study, performance on the story recall test, which involves an attentional component showed no differences, perhaps indicating that attentional impairment related to hypersomnolence was not a factor, and that primary cerebral changes related to hypoventilation may be in play. Investigation of sleep symptoms Nocturnal oximetry While oximetry may be used to detect both intermittent and sustained nocturnal hypoxemia, during both REM and NREM sleep [60], it does not provide any information about sleep quality or architecture. Not only is REM sleep the period of greatest vulnerability for developing nocturnal hypoventilation, a marked reduction of REM sleep duration has been shown to be associated with reduced survival in ALS [31]. Since a significant number of patients
Please cite this article in press as: Ahmed RM, et al., Sleep disorders and respiratory function in amyotrophic lateral sclerosis, Sleep Medicine Reviews (2015), http://dx.doi.org/10.1016/j.smrv.2015.05.007
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with ALS fail to achieve REM sleep during diagnostic investigations [60], oximetry alone could underestimate the severity of respiratory compromise. Furthermore, oximetry measures oxygen saturation only and not hypoventilation per se. Polysomnography Polysomnography (PSG) provides a more detailed assessment of the respiratory and non-respiratory factors contributing to nonspecific complaints of poor or unrefreshing sleep, and is useful in providing prognostic information in this patient group [61]. However, while attended PSG is a valuable tool for distinguishing the underlying cause of reported sleep disturbances, it can also be a difficult undertaking for non-ambulant patients with high care needs. Resources for attended PSG are also limited in some settings. Unattended diagnostic PSG recording in the patient's home is one potential alternative. Split night PSG studies (diagnostic and treatment) within a single night are widely used in the management of patients with simple obstructive sleep apnea. However, this approach is frequently inconclusive for adequately assessing nocturnal hypoventilation and completing titration of non-invasive ventilation in patients with ALS due to poor sleep efficiency and the absence of REM sleep [62]. Whether sleep disordered breathing is investigated using oximetry, PSG or polygraphy in a sleep laboratory or in the patients' home, simultaneous monitoring of transcutaneous or end-tidal carbon dioxide should be undertaken to better detect sleep hypoventilation [63]. Treatment of sleep and respiratory symptoms Whilst there is currently no cure for ALS, the clinical focus remains on measures to prolong survival and improve patient quality of life. Management of sleep and respiratory symptoms is central to this. Pharmacological Many neuroprotective strategies have been explored in ALS, with a dearth of successful agents identified, especially in humans by comparison with experimental evidence [64]. Riluzole, a glutamate and excitatory regulator thought to stimulate glutamate uptake, has demonstrated a partial benefit on survival in the order of 3 months (Class 1 evidence) [65,66], with benefits accentuated by use of a specialized multidisciplinary setting [67]. It has also been shown that Riluzole has some properties for the treatment of experimental hypoxia-induced gasping [68] and duration of REM/ NREM sleep [69]. Nocturnal ventilation and non-invasive ventilation In a small number of ALS cases, OSA is the predominant form of SDB, which may respond to CPAP at least initially. However many patients find single level pressure difficult to tolerate, particularly when diaphragmatic and abdominal muscle weakness becomes more advanced. Consequently, non-invasive positive pressure ventilation (NIV) remains the mainstay of respiratory treatment for patients with ALS [70e72]. Bilevel ventilation devices are most commonly used as initial therapy (see below). Using NIV, improvements in symptoms, quality of life and survival are achievable [73e75], although these benefits are primarily limited to those with normal to moderate bulbar weakness [76]. While patients with severe bulbar dysfunction are less likely to tolerate [77,78] or benefit from NIV [76,79] relief of sleep-related symptoms may still occur [76]. Therefore, the available evidence is in favour of offering NIV to all patients with ALS, including those with poor bulbar function [75].
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When to introduce non-invasive ventilation The most appropriate time to introduce NIV in ALS has not been determined. In the only randomized trial to date, criteria for commencing NIV were either orthopnea with MIP < 60% predicted or symptomatic daytime hypercapnia (PaCO2 >45 mmHg). However, an earlier study found that patients with orthopnea but without daytime hypercapnia or nocturnal desaturation responded to NIV in a similar fashion. In addition, when the more rigid criteria for initiating therapy were used in a randomized trial, 6 of the 19 patients allocated to standard care died within the first 2 weeks of the study [76], suggesting advanced and unstable respiratory compromise was already present by the time symptoms and moderate alterations in lung function were identified. Current recommendations for considering a trial of NIV include any of the following: PaCO2 >45 mmHg, MIP
