Sleep–Wake Problems in Patients with Amyotrophic Lateral Sclerosis: Implications for Patient Management

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REVIEW For reprint orders, please contact: [email protected] Sleep–wake problems in patients with amyotrophic lateral sclerosis: implications for patient management

Daniele Lo Coco*1,2, Emanuele Cannizzaro3, Rossella Spataro1, Alfonsa Claudia Taiello1 & Vincenzo La Bella1

Sleep–wake problems in patients with amyotrophic lateral sclerosis (ALS) are common, although they are unrecognized and understudied.

The frequency of poor sleep increases with disease progression, especially because of the invariable involvement of respiratory muscles and the diaphragm, and normal rapid eye movement sleep-related changes in ventilation are magnified as a result of muscle weakness.

Practice Points Practice Sleep disorders may also be the consequence of comorbid psychiatric conditions (i.e., anxiety and depression), spasticity, pain, choking, sialorrhea, poor secretion clearance, fasciculations, cramps, nocturia and reduced mobility.

Sleep disturbances in ALS include insomnia, obstructive and/or central sleep-disordered breathing, nocturnal alveolar hypoventilation and restless legs syndrome (RLS).

Insomnia in patients with ALS should be treated in a multifaceted approach, considering both pharmacological and nonpharmacological treatment. Additional caution should be used in patients with substantial respiratory muscle weakness not receiving ventilatory support.

Sleep-disordered breathing can be effectively treated with noninvasive ventilation, and hence, all patients with ALS should be carefully and repeatedly evaluated using specific diagnostic tests such as nocturnal oximetry and/or polysomnography.

RLS can be a cause of poor sleep in patients with ALS. When moderate or severe, RLS can disrupt sleep, thus causing daytime dysfunction. The diagnosis of RLS in patients with ALS could be challenging, especially for physicians unfamiliar with sleep-related disorders. RLS must be carefully distinguished from many mimic conditions such as neuropathic pain syndromes, leg cramps and spasms, stiffness and discomfort from spasticity or prolonged fixed position.

1ALS Clinical Research Center, Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BioNeC), Università di Palermo, Palermo, Italy 2Sleep Disorders Clinic, Dipartimento di Neuroscienze, Ospedale Civico – ARNAS, Piazza N. Leotta, 4 – 90129, Palermo, Italy 3Dipartimento di Scienze Farmacologiche, Università di Palermo, Palermo, Italy *Author for correspondence: Tel.: +39 091 666 3117; Fax: +39 091 666 3006; [email protected] part of

SUMMARY Sleep–wake problems are frequent, although unrecognized, complications of amyotrophic lateral sclerosis (ALS). Sleep disorders such as insomnia, sleep-disordered breathing and restless legs syndrome have all been reported in patients with ALS, despite the limited number of studies and the small populations investigated so far. Sleep disturbances gradually worsen with disease progression, suggesting a relationship between the severity of disease and the neurodegenerative process. However, poor sleep can also be a consequence of several disturbances such as anxiety, depression, pain, choking, sialorrhea, fasciculations, cramps, nocturia and the inability to get comfortable and move freely in bed. Sleep disorders may have many reflections on patients with ALS, including excessive daytime somnolence, fatigue, impaired cognition, reduced quality of life and survival. This article reviews the recent literature on sleep–wake problems in patients with ALS, focusing on the implications for patient management.

Amyotrophic lateral sclerosis (ALS) is a neuro- difficulties turning in bed. Patient disability degenerative disease characterized by progressive was the most important variable associated with degeneration of motor neurons in the primary poor sleep quality [4]. motor cortex, corticospinal tracts, brainstem and In another case series study on 24 patients spinal cord, leading to muscle atrophy, paralysis with ALS, it was found that insomnia symptoms and death because of respiratory failure within were present in 25% of patients, and patients in 2–5 years, even though approximately 10% of a terminal state had a higher frequency of sleep ALS patients survive for 10 or more years [1]. disturbances (up to 48%) [5]. Although it is well known that patients with Ferguson and colleagues reported that ALS frequently report sleep-related complaints most of the patients included in their small (e.g., insomnia, disturbed sleep, frequent noc- case series study complained of difficulty ini- turnal awakenings, nightmares, morning head- tiating and maintaining sleep (71 and 100%, aches and daytime sleepiness), these symptoms respectively) [6]. have usually been ascribed to disturbed noctur- SDB can be observed in patients with ALS, nal gas exchange and hypoventilation [2,3]. As especially in the advanced phase of the disease. a result, sleep disturbance is among the least Mild-to-moderate obstructive sleep apnea (OSA) studied aspects of ALS and, in the clinic, gen- cases have been reported in some observational erally receives little attention from most neu- studies, as well as central apneas, while noctur- rologists. It has really only been in the last two nal hypoventilation, primarily related to pathol- decades that investigation has been directed ogy in the cervical spinal cord a-motor neurons, towards understanding the nature and pattern increases as the disease progresses [4,6–15]. of sleep disturbances in ALS, especially those In our experience, however, only a minority of related to sleep-disordered breathing (SDB) and patients complained about their sleep problems nocturnal hypoventilation. This article reviews spontaneously, while the majority complained the recent literature on sleep–wake problems in when asked [4]. patients with ALS, focusing on the implications In line with the aforementioned findings, for patient management. polysomnographic examinations usually show abnormalities such as increased frequency of How common are sleep disturbances SDB, reduced sleep efficiency, fragmented in ALS? sleep architecture with reduced slow wave A recent case–control survey from our group sleep, as well as reduced and fractured rapid suggests that sleep disturbances occur in 59% eye movement (REM) stages, and frequent of patients with ALS, and 28% reported mod- arousals [4,6,10,12]. erate-to-severe dysfunction [4]. In 42%, sleep complaints appeared after disease onset, and The nature of sleep disturbance in ALS the most common sleep problems reported The most frequent sleep disturbances in patients were nocturia (54%), difficulties staying asleep with ALS are insomnia, excessive nocturnal (48%), nocturnal cramps (45%), snoring (33%) motor activity and SDB. Other, less studied, and difficulties falling asleep (32%). Twenty possible causes of sleep–wake disturbances are three patients (23%) reported excessive daytime circadian rhythm disorders (CRDs) and REM sleeping, and 52 (52%) patients complained of sleep behavior disorder (RBD).

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Insomnia The prevalence of CRD in the general popu- Insomnia occurs when patients, despite adequate lation is unknown, and, at present, there is no opportunity, have trouble with sleep initiation study that specifically investigated the possibility (initial insomnia), sleep maintenance (middle of higher rates of CRD in patients with ALS, or insomnia), or arising earlier than desired (termi- supporting an association or a causal relationship nal insomnia), coupled with impaired daytime between the two conditions. However, as people functioning. Patients could also experience unre- age, their circadian rhythms become weaker, freshing sleep, that is, feeling tired and sleepy desynchronized and lose amplitude [24]. It could be after waking in the morning [16]. speculated that the degenerative process, as seen in The prevalence of insomnia with daytime ALS, could contribute in disrupting the function impairment may range, in the general popula- of the biological pacemaker. Moreover, the exter- tion, from 10 to 15%, and from 30 to 100% nal cues that are necessary to entrain the circadian in patients with neurodegenerative diseases [17]. rhythm of sleep–wake cycles may be weak or miss- In our recent survey, the prevalence of initial ing in patients with ALS, especially in advanced insomnia in the population of patients with ALS phases of the disease. Patients with ALS may also was 32%, the prevalence of middle and terminal have a reduced time-of-light exposure because of insomnia was 48%, and unrefreshing sleep was their physical limitations and this could have an reported by 29% of patients [4]. effect on the circadian rhythm of their sleep–wake Physicians should be aware of common symp- cycles. Other possible causes of CRD may also be toms seen in ALS that may precipitate insomnia. present in patients with ALS, as well as in other Indeed, nocturia and difficulties turning in bed populations of similar age [24], although these can cause early morning awakening, disturbed should be differentiated from irregular sleep–wake sleep and increased sleep fragmentation. Muscle cycles (named ‘sundowning’) observed in patients cramps, spasticity, pain, and restless legs syn- with Alzheimer’s disease. drome (RLS) symptoms may cause difficulty in initiating and maintaining sleep, and SDB RLS & periodic limb movements in sleep can fragment sleep architecture and cause day- RLS is a disorder with sensory and motor compo- time somnolence. Patients with bulbar impair- nents. The International Restless Legs Syndrome ment could also present problems with choking, Study Group established four essential clinical sialorrhea and poor secretion clearance [4,6,18]. criteria defining RLS: Moreover, the role of psychiatric conditions, An urge to move, usually due to uncomfortable such as anxiety and depression, in determining sensation in the legs; insomnia should not be underestimated [19]. Polypharmacy could also be a cause of second- The urge in the legs improves with movement ary insomnia in patients with ALS. Although of the legs; there is no known direct effect of riluzole on sleep function, this drug may induce slight som- Symptoms worsen at rest; nolence and it has also been shown to increase Symptoms often worsen in the evening or at slow-wave sleep in rats [20–22]. Moreover, many night [25]. of the medications that are prescribed for medical conditions that could co-occur in patients When severe, RLS disrupts sleep, caus- with ALS may also contribute to, or even cause, ing excessive daytime sleepiness, depression, insomnia, such as antihypertensives, respira- insomnia and fatigue [26]. In the general popu- tory medications, chemotherapy, hormones or lation, RLS frequency varies from 5 to 10%, but psychotropics (e.g., selective serotonin-reuptake increased RLS frequency (up to 55% of cases) inhibitors, atypical antidepressants and mono- has been reported in many neurodegenerative amine oxidase inhibitors) [23,24]. Figure 1 sum- disorders such as Parkinson’s disease, spinocer- marizes the many potential contributing factors ebellar ataxias, Huntington’s disease and heredi- that may cause insomnia in patients with ALS. tary spastic paraparesis [27]. Severe RLS is associated with significant sleep loss with patients Circadian rhythm disorders reporting as little as 3–5 h, thus, causing sleep CRDs can occur from a mismatch between the deprivation and daytime dysfunction. internal interval and the external environment In a recent case–control study, we found an regarding the timing and duration of sleep [16]. increased frequency of RLS in a population of

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Sleep Neurodegenerative Aging disordered process breathing

Spasticity Anxiety

Insomnia Cramps Depression

Nocturia

Reduced Sialorrhea Polypharmacy mobility

Figure 1. Contributing factors that may cause insomnia in patients with amyotrophic lateral sclerosis.

76 patients with ALS. RLS was present in 25% REM sleep behavior disorder of patients (and in 8% of age- and sex-matched RBD is a parasomnia in which the skeletal muscle controls), and patients with ALS and RLS dem- atonia, normally found in REM sleep, is absent, onstrated a shorter history of RLS complaints replaced by increased electromyographic tone and a higher frequency of symptom occurrence on submental or limb leads. As a consequence, [28]. Moreover, patients with ALS and RLS patients with RBD exhibit injurious or disrup- frequently reported insomnia complaints and tive behavior in REM sleep, and may act out showed increased functional disability. Iron their dreams. Although RBD can be idiopathic, status was within the normal range [28]. it frequently arises secondary to a neurological Another group also confirmed the increased disease with brainstem involvement, most com- frequency of RLS symptoms in patients with monly a-synucleinopathies, with a prevalence ALS (18.8%), and they suggested that this ranging from 40 to 100% [32]. Excluding three relationship may be mediated by reduced single cases reported in the literature [33,34], there mobility, which would aggravate the sensa- are, at present, no studies that specifically exam- tion of motor restlessness, normally relieved ined abnormal motor activity during sleep that by movement [29]. could be indicative of RBD in patients with ALS. It should be noted, however, that distinguish- ing RLS from other motor and sensory symp- Sleep-disordered breathing toms in ALS can be challenging since patients SDB, including OSA, central sleep apnea and with ALS often complain of leg spasms and nocturnal hypoventilation, are a group of dis- cramps or leg discomfort, which is worse after orders characterized by disordered respiration immobility. Additional RLS mimics that must during sleep [35]. OSA is characterized by repeti- be excluded are neuropathic pain syndromes, tive episodes of cessation of breathing (apneas) leg cramps and spasms, stiffness from spastic- or partial upper airway obstruction (hypop- ity or prolonged fixed position. In these cases, neas) in the presence of respiratory effort, that it is important to make sure that the patient are often associated with reduced blood oxygen feels a discomfort in the affected limb, that the saturation. Hypoventilation is defined by an

movements of the limbs are voluntary, bring abnormally elevated PaCO2 and high serum at least some relief, and are maximal in the bicarbonate levels with an associated reduction

evening or at night [30,31]. Moreover, in case of of PaO2. SDB is a common respiratory diosor- doubt, a polysomnographic assessment, show- der, affecting 2–4% of adults. Its prevalence ing increased periodic leg movements in sleep, increases with age (especially OSA), and it has could be of help. also been frequently reported in patients with

318 Neurodegen. Dis. Manage. (2012) 2(3) future science group Sleep–wake problems in patients with ALS: implications for patient management Review neurodegenerative disorders such as multiple Consequences of poor sleep system atrophy or Alzheimer’s disease [36]. Although the consequences of poor sleep in Patients with SDB may present with daytime patients with ALS have not yet been extensively sleepiness, unrefreshing sleep, morning headache, investigated, poor sleep may lead to excessive nocturnal apneas, gasping, choking, snoring, daytime sleepiness, which results from multiple fatigue, poor concentration, mood changes and and recurrent nighttime arousals that cause sleep nocturia – all complaints frequently experienced fragmentation [24]. Other common manifesta- in ALS. tions of the daytime sleepiness include uninten- SDB is common in ALS with the progression tional napping and falling asleep at inappropriate of the disease, owing to the result of progressive times during the day, causing social and occupa- involvement of respiratory muscles (particularly tional difficulties as well as reduced vigilance[24] . the diaphragm). However, SDB can occur even Excessive daytime sleeping has also been linked when respiratory muscle function is only mildly to increased risk of falls, cognitive dysfunction affected and patients present normal daytime and impaired memory [47,48]. gas exchange [6,10,37]. Moreover, a proportion Sleep disturbances could cause a decreased of patients, although exhibiting a normal dia- quality of life, and could be responsible for phragmatic function, may show mild periodic psychiatric symptoms such as anxiety and oxygen desaturations during sleep, which could depression [24]. represent an early sign of impaired central neural Furthermore, poor sleep has recently been control of respiration or diaphragmatic fatigue associated with fatigue, especially in the pres- [12]. Nocturnal hypoventilation is the most com- ence of nighttime complaints such as nocturia mon form of SDB in ALS, representing a relevant and muscle cramps [49]. As in other neurologi- milestone in the natural history of this illness, cal disorders known to be associated with sleep and causing severe sleep fragmentation and day- complaints (e.g., multiple sclerosis, a-synucle- time sleepiness. Nocturnal hypoventilation is inopathies or tauopathies), sleep disturbances particularly severe during REM sleep, when all could result in a potential increase in disability, postural and accessory muscles are physiologi- although this has not yet been proven in large cally atonic, and only the diaphragm, which may studies. itself be impaired, is left to sustain ventilation and Finally, respiratory impairment and noctur- overcome any upper airway resistance [6]. nal hypoventilation are associated with reduced Sleep apnea seems to occur less frequently survival, and there is considerable evidence that than hypoventilation, but there is no agreement noninvasive ventilation (NIV) could be useful on its prevalence, since some observational stud- to alleviate respiratory symptoms, to extend sur- ies reported high rates of OSA in patients with vival, and to improve quality of life and cognitive ALS, whereas others have found the opposite functions in most patients [41,50–58]. [4,6,10,11,37,38]. Bulbar impairment, however, has not been related to the increased risk of OSA, Assessment & treatment of sleep probably because of the inability of patients disturbances in ALS with respiratory muscle weakness to generate Treatment of insomnia an inspiratory pressure greater than the upper Insomnia in patients with ALS should be treated airway closing pressure [6]. On the other hand, in a multifaceted approach, considering differ- some authors observed central apneic events more ent possible therapies that should be tailored to frequently, and they related this finding to respi- the single patient’s needs. ratory muscle weakness, especially during REM Treatment options for insomnia include basic sleep [6,8,10,11,38]. sleep hygiene education, psychological and Since nocturnal oximetry is easily performed behavioral interventions and pharmacotherapy. and can be executed domiciliary, it is commonly Sleep hygiene education is intended to provide used in clinical practice for the evaluation of information regarding lifestyle (i.e., diet, exer- respiratory involvement in patients with ALS, cise, alcohol and caffeine intake) and environ- to predict survival, and as a guide to initiate mental factors (i.e., light, noise and tempera- mechanical ventilation [39–44]. Pulmonary func- ture) that may either interfere with, or promote, tion parameters, such as sniff nasal inspiratory better sleep [59,60]. Psychological and behavioral pressure and capnography, could also be useful therapies for insomnia include sleep restriction, to detect SDB in these patients [45,46]. stimulus-control therapy, relaxation training,

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cognitive strategies, and a combination of those Other drugs frequently used to treat insomnia methods, referred to as cognitive behavioral are sedating antidepressants such as trazodone, therapy [17]. Although there are many studies amitriptyline, doxepin and mirtazapine, partic- attesting that patients with primary insom- ularly for sleep-maintenance insomnia, and in nia benefit from these treatments [61], at pres- patients with comorbid depression [64]. However, ent, there are no studies that have specifically it must be noted that treatment of severe mood investigated the effects of nonpharmacological instability in the context of insomnia should be approaches on insomnia complaints in patients treated separately and independently for bet- with ALS. ter long-term efficacy and reduction of relapse With regards to pharmacotherapy, despite of either sleep or mood condition. Moreover, the high frequency of sleep complaints in our additional caution should be posed to the anti- ALS population, we observed a relatively low cholinergic side effects such as dry mouth, use of sleeping medications, which was com- constipation, urinary retention and confusion. parable to that of healthy controls [4]. We related this finding to the low rate of patients Treatment of SDB spontaneously reporting sleep–wake problems, The most common and proven treatment of but we also inferred that a cautious approach SDB in ALS is NIV. Continuous positive air- from physicians, concerned about possible way pressure is the preferred appliance in the negative effects of hypnotics on respiratory case of OSA, however, since the most common function, could have also played a role [4]. disturbance in ALS is nocturnal alveolar hypo Pharmacological intervention should only be ventilation, patients are usually started with noc- introduced if required, and if the sleep disor- turnal bilevel positive airway pressure ventila- der is comorbid with a medical or psychiatric tion. All patients with ALS can benefit from NIV condition such as pain, depression, anxiety or therapy, and a trial with this appliance should RLS, the underlying disease has to be treated never be discouraged, even if some authors have [17]. Regarding sleep medications, there are ten concerns that marked bulbar involvement could medications approved by the US FDA for the be associated with reduced tolerance and maybe treatment of insomnia (Table 1). Besides the survival [51,53]. As in other patient populations, careful consideration of side effects (e.g., seda- NIV compliance could be an issue, but our tion, daytime sleepiness, rebound insomnia, group has recently demonstrated that intensive addiction, tolerance, risk of falls and cognitive educational training and adaptation on NIV, impairment), these drugs should be used with when performed in a hospital multidisciplinary additional caution in patients with substantial setting, increases compliance and tolerance over respiratory muscle weakness not receiving ven- time, even in those patients with severe bul- tilatory support, because of their potential to bar impairment [65]. NIV could improve sleep reduce ventilation [17,62,63]. architecture, daytime sleepiness, self-reported

Table 1. US FDA-approved hypnotics for insomnia. Name of the agent Dose (mg) Half-life (h) Duration Indications Benzodiazepines Flurazepam 15–30 48–120 L Initial, middle and/or terminal insomnia Quazepam 7.5–15 41 L Initial, middle and/or terminal insomnia Estazolam 1–2 10–24 I Middle and/or terminal insomnia Temazepam 7.5–30 3.5–18 I Middle and/or terminal insomnia Triazolam 0.125–0.5 1.5–5.5 S Initial insomnia Nonbenzodiazepines Zaleplon 10 0.9–1 S Initial insomnia Zolpidem 5–10 2.5 S/I Initial insomnia Zolpidem ER 12.5 2.8 S/I Initial and/or middle insomnia Eszopiclone 2–3 6 I Initial and/or middle insomnia Melatonin receptor agonists Ramelteon 8 1.2–6 S Initial insomnia ER: Extended release; I: Intermediate acting; L: Long acting; S: Short acting.

320 Neurodegen. Dis. Manage. (2012) 2(3) future science group Sleep–wake problems in patients with ALS: implications for patient management Review symptoms such as snoring, choking, and gasp- lack of objective reports or polysomnographic ing, could ameliorate cognitive impairment, data. Most of these knowledge gaps, in our opin- could improve nocturia complaints, reducing ion, are the reflection of the limited knowledge the number of voids per night. Moreover, NIV and the reduced expertise in sleep medicine of reduces or eliminates OSA and nocturnal oxygen many physicians directly involved in the care of desaturations, thus ameliorating and supporting patients with ALS (i.e., neurologists and pulmo- respiratory function. nologists). However, as it has been the case in Parkinson’s disease, sleep dysfunction, as well as Treatment of other sleep disturbances other nonmotor symptoms, could gain increas- Although no evidence-based treatment exists for ing attention and clinical value in the scientific RLS in patients with ALS, if RLS is documented community as larger evidence is gathered. it should be treated with a dopamine agonist as Among the areas of interest that could deserve first-line therapy. Pramipexole and ropinirole are more attention in future studies, particular rel- both FDA-approved for the treatment of RLS evance should be devoted on the specific contri- in the general population, although physicians bution of the various clinical pictures character- should pay attention to the potential risk of aug- istic of the disease. In particular, investigating mentation (i.e., the worsening of RLS symptoms the different roles of bulbar dysfunction (causing with an earlier occurrence in the evening or an sialorrhea, drooling and dysphagia) and upper increase in symptom severity), that is a class- and lower motor neuron involvement (respon- specific and very potentially dangerous aspect sible for spasticity, reduced mobility, fascicu- of the dopamine-agonists treatment. Other non- lations and cramps) on nighttime complaints FDA-approved therapies for RLS include the use could reinforce our knowledge in this subject, of opioids, gabapentin and benzodiazepines. and provide interesting insights with potential Moreover, when the patient’s ferritin is less positive reflections on the clinical management than 45–50 µg/l, oral iron treatment is usually of these patients. indicated as a supplemental treatment [66]. Moreover, although they have not been spe- The goal of therapy for CRD is to resynch cifically tested in patients with ALS so far, some ronize the circadian clock with the desired 24-h recently introduced diagnostic and treatment light–dark cycle. For these patients, chrono devices, such as ambulatory polysomnographic therapy, phototherapy and melatonin could monitoring, actigraphic devices, auto servo- be tried, since they have been employed in the ventilation and autocontinuous positive airway general population to shift the circadian rhythm pressure devices, as well as smart phone applica- back to a normal range [24]. tions, could be implemented in the near future The first-line therapy for treating RBD is for treating and monitoring patients with ALS. clonazepam (0.5–1 mg at bedtime). Although Further studies are also needed to inves- its specific mechanism of action in RBD is tigate the causes of disturbed sleep in ALS. unknown, clonazepam is effective in almost Neurodegenerative diseases result from pro- every patient, with little evidence of tolerance gressive deterioration of neuronal cells that may or abuse. However, caution is needed regarding eventually lead to CNS-related dysfunction side effects, including sedation and the potential including sleep disorders, and ALS is no excep- for respiratory depression. On the other hand, tion. Therefore, the pathogenesis of sleep dis- selective serotonin-reuptake inhibitors and other turbances may be secondary to direct structural antidepressants can precipitate RBD symptoms, alterations of neurons and networks regulating and should be avoided. sleep–wake cycles, but could also be an indi- rect consequence of several disturbances such Conclusion & future perspective as anxiety, depression, spasticity, pain, choking, Sleep–wake disturbances are common complica- sialorrhea, poor secretions clearance, fasciculations in ALS that should be recognized promptly tions, cramps, nocturia and the inability to get as they are associated with significant morbidity comfortable and move freely in bed [4,6]. and can be successfully treated. However, the Finally, additional work by our group is prevalence and strength of this association has focused in identifying the reflections of sleep not been determined on a large-scale level, and abnormalities on quality of life and the impact there are still a small number of studies dealing of their optimal management on the patients and with this subject. Moreover, there is a relative their caregivers.

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Financial & competing interests disclosure employment, consultancies, honoraria, stock ownership or The authors have no relevant affiliations or financial options, expert testimony, grants or patents received or involvement with any organization or entity with a finan- pending, or royalties. cial interest in or financial conflict with the subject matter No writing assistance was utilized in the production of or materials discussed in the manuscript. This includes this manuscript.

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