Comorbid Sleep Disturbances in Neurologic Disorders

Review Article

Address correspondence to Dr Yo-El S. Ju, Washington Comorbid Sleep University in St. Louis, 600 South Euclid Ave, Box 8111, St. Louis, MO 63110, Disturbances in [email protected]. Relationship Disclosure: Dr Ju has received personal Neurologic Disorders compensation for serving as a speaker and moderator for the American Academy of Yo-El S. Ju, MD, MSCI; Aleksandar Videnovic, MD, MSc, FAAN, FAASM; Neurology, as a speaker for Bradley V. Vaughn, MD, FAAN, FAASM the American Academy of Sleep Medicine and the World Association of Sleep Medicine, and as a consultant of C2N ABSTRACT Diagnostics. Dr Ju has Purpose of Review: This article provides a review of disturbances of sleep comorbid received research/grant support from the National with common neurologic disorders. Institutes of Health and as Recent Findings: A wide variety of neurologic disorders are frequently complicated principal investigator of a by comorbid sleep disturbances. In many cases, a bidirectional relationship appears to study for Philips Respironics. Dr Videnovic serves on occur between sleep function and the neurologic disease, such that treatment of the editorial board of comorbid sleep disturbances may improve the symptoms of the neurologic disease. Parkinsonism & Related Summary: Neurologic disorders are often associated with abnormalities of sleep. Disorders and has received personal compensation for Sleep influences the severity of both epilepsy and headache, and treatment of serving as chair of the data comorbid sleep disorders may improve seizure and headache frequency. Alzheimer and safety monitoring board disease is characterized by circadian phase delay and poor nighttime sleep and is of Acorda Therapeutics and for serving on the data and strongly associated with obstructive sleep apnea. Parkinson disease is associated with safety monitoring board of several sleep disorders, including insomnia, restless legs syndrome, rapid eye Wilson Therapeutics. movement (REM) sleep behavior disorder, daytime hypersomnia, and sleep- Dr Videnovic has received research grants from the disordered breathing. Hypoventilation in amyotrophic lateral sclerosis and other National Institute of neuromuscular disorders often presents initially with sleep problems, and treatment Neurological Disorders and with noninvasive ventilation improves survival and quality of life. Stroke and receives royalties from Springer International Publishing AG. Dr Vaughn Continuum (Minneap Minn) 2017;23(4):1117–1131. has received personal compensation as a speaker for the American Academy of Neurology, American Academy of Sleep Medicine, INTRODUCTION SLEEP AND EPILEPSY and Medical Education Sleep is a complex brain-generated Sleep provides an opportunity to Resources and receives royalties from Medlink behavior. Therefore, unsurprisingly, examine and potentially improve epi- Neurobase and UpToDate, neurologic diseases frequently are lepsy. A variety of physiologic re- Inc. Dr Vaughn has received personal compensation for associated with sleep disturbances. percussions of sleep influence the serving as chair of the sleep This article discusses the most com- electric and pathophysiologic mani- medicine examination committee of the American monly encountered comorbid sleep festations of epilepsy. These range Board of Internal Medicine. disorders in neurologic practice, with from promotion or inhibition of epi- Unlabeled Use of particular attention to the interaction leptic events to the theoretic effects Products/Investigational Use Disclosure: between sleep function and neurologic of kindling in epileptic pathophysiol- Dr Ju discusses the unlabeled/ disease. The article details sleep disor- ogy. In addition, epilepsy can cause investigational use of trazodone to treat comorbid ders in epilepsy, headache, Alzheimer further sleep disruption and changes sleep disturbances in disease (AD), Parkinson disease (PD), in sleep architecture. Likewise, the dementia. Drs Videnovic and and amyotrophic lateral sclerosis treatment of epilepsy can impact sleep. Vaughn report no disclosures. * 2017 American Academy (ALS). Key sleep-related features in These dynamic relationships lead to of Neurology. neurologic disorders are summarized patients with epilepsy frequently hav- in Table 10-1. ing sleep problems.

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TABLE 10-1 Common Comorbid Sleep Comorbidities in Neurologic Diseases

Common Neurologic Common Sleep Presenting Targeted Treatments Disease Comorbidities Symptoms Investigations and Notes Epilepsy Insomnia, Sleep fragmentation Polysomnography Treat underlying obstructive with full EEG seizure disorder sleep apnea and video Headache Insomnia, Sleep fragmentation Polysomnography Treat sleep apnea, obstructive improve sleep hygiene sleep apnea (see Table 10-2 for specific syndromes) Alzheimer Obstructive Snoring, apneas, Polysomnography, Positive airway disease sleep apnea, sundowning, actigraphy pressure if obstructive delayed nighttime wandering, sleep apnea circadian phase daytime sleepiness Parkinson Insomnia, rapid Early morning Polysomnography Adjust Parkinson disease eye movement awakenings, dream with video EEG disease medications, sleep behavior enactment, restless melatonin/clonazepam disorder, restless legs, daytime legs syndrome, sleepiness hypersomnia, sleep-disordered breathing Neuromuscular Hypoventilation, Orthopnea, morning Oximetry, Volume-targeted disorders obstructive headache, hypersomnia, polysomnography, noninvasive sleep apnea sleep fragmentation pulmonary function ventilation or tests, arterial bilevel positive blood gas airway pressure (see Table 10-3 for specific disorders) Stroke Obstructive Snoring, witnessed Polysomnography Central sleep apnea sleep apnea apneas, hypertension may resolve in and central the immediate apneas poststroke period Multiple Obstructive Multiple sclerosisYrelated Polysomnography Sleep disorders are sclerosis sleep apnea, fatigue associated with restless legs cognitive dysfunction syndrome EEG = electroencephalogram.

KEY POINT The influence of sleep can be exam- selective sleep stage deprivation stud- h Seizures are more ined by the effect of total sleep and the ies have been performed in humans, likely to start during effect of each stage. Since Hippocrates, studies in animals suggest the selective nonYrapid eye patients with epilepsy have been loss of rapid eye movement (REM) movement sleep, whereas rapid eye warned to avoid sleep deprivation, and sleep may enhance the kindling pro- movement sleep several studies show the provocative cess and cause progression in intracta- 3 appears to be protective nature of sleep deprivation on epileptic bility of focal-onset seizures. Likewise, 1 against seizures. events. In addition, oversleeping ap- the sleep stage may influence seizure pears to increase the occurrence of onset. Seizures are more likely to start epileptic seizures.2 Although no good during non-REM sleep, whereas REM

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT sleep appears to be protective against or discharges. Some primary generalized h 4 Diagnosis and treatment seizures. Similarly, interictal discharges epilepsies, especially those including my- of comorbid sleep are more likely in non-REM sleep, with oclonus, are associated with seizures apnea may offer an the greatest increase in frequency, soon after awakening, indicating that opportunity to improve topography, and localization noted seizure generation is somehow more seizure frequency and with the approach of deeper stages of prominent during the sleep-to-wake tran- quality of life in patients non-REM sleep.5 REM sleep is the state sition period. with epilepsy. least likely to have interictal discharges, Epilepsy also produces changes in and these discharges are most re- sleep. Seizures are noted to cause stricted to near the epileptic focus; postictal somnolence, but also evoke thus, REM sleep offers an opportunity more wake after sleep onset, sleep for better localization of epileptic foci.6 fragmentation, and REM sleep suppres- Although these observations are clear, sion during the sleep period follow- the underlying reason for the differ- ing the seizure. This effect appears to ence of topography of the interictal extend beyond frank seizures. Interictal discharges is still somewhat unclear. discharges also cause sleep fragmenta- Most theories rest on the hypothesis tion, potentially by disrupting signals that more neurons are in the resting involved in sleep circuitry, thus disrupt- state in non-REM sleep and thus are ing the physiologic coordination of available for recruitment into the dis- sleep. This disruption may have some charge; however, during REM sleep, downstream effect as it has been overall greater neuronal firing occurs, hypothesized that nighttime discharges and neurons are less available to be may influence daytime learning.7 Re- recruited into the interictal firing. cent studies have shown correlations Some epilepsies are specifically between nighttime seizure activity and related to sleep.6 Benign epilepsy of complaints of nighttime disruption and childhood with central temporal spikes daytime symptoms.8 Similarly in adults, is typically associated with seizures patients with frequent interictal dis- manifesting as focal spasms of the face charges during sleep had more day- or hand with jerking, occurring in the time symptoms of sleepiness, and first one-third of the night. These events antiepileptic drugs may help decrease classically start in non-REM sleep and, the frequency of nocturnal discharges for many patients, the interictal dis- and improve daytime symptoms.6 charge appears only during sleep. Nearly two-thirds of patients with Similarly, autosomal dominant noctur- epilepsy note sleep problems.6 These nal frontal lobe epilepsy is also seen as symptoms translate into a higher pre- a variety of brief and occasionally valence of underlying sleep issues. violent hyperkinetic events occurring Polysomnographic examination of pa- from non-REM sleep. This disorder tients with epilepsy showed a high is associated with an abnormality in prevalence of obstructive sleep apnea the nicotinic receptor complex, and (OSA), a disorder in which the upper seizures may be frequent and often airway collapses during sleep, often occur only during sleep. These pa- accompanied by sleep fragmentation.9 tients appear to respond to carbamaz- Diagnosis and treatment of comorbid epine or lamotrigine; however, a portion sleep apnea may offer an opportunity remains intractable. Other epilepsy syn- to improve seizure frequency and dromes such as Panayiotopoulos syn- quality of life in patients with epilepsy. drome and Landau-Kleffner syndrome Several case series and one random- are also associated with nocturnal events ized double-blind trial have shown that

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KEY POINTS h Sleep deprivation and addressing comorbid sleep problems sleep is even greater. Nearly 86% of excessive sleep increase was associated with improvement in patients with episodic migraine note 6 headaches in both intractable epilepsy. poor sleep quality, and poor sleep was children and adults. Many medications used to treat associated with increasing headache h epilepsy influence sleep, yet most need frequency and headache-related dis- Hypnic headaches 11 (sometimes called further study in both patients with ability. Likewise, poor sleep hygiene alarm clock headaches) epilepsy and in normal controls. Tradi- was noted as a frequent perpetuating abruptly awaken tional medications such as phenobarbi- agent in transformed migraine, and patients after 1 to tal, carbamazepine, phenytoin, and the improvement of sleep-promoting 3 hours of sleep and valproate have a soporific effect, but behaviors reverted the transformed may respond to caffeine they also may produce significant migraine back to episodic migraine.12 or, if frequent, changes in overall sleep architecture, This relationship between headaches treatment with lithium. such as decreased REM sleep or in- and sleep extends to those with primary creased sleep fragmentation. Pregabalin sleep disorders. Patients with insomnia and gabapentin both appear to have a have a 50% greater likelihood of benefit by increasing slow-wave sleep having headaches and more severe and may improve sleep and attention in headaches. Similarly, bed partners of patients with epilepsy and insomnia.6 habitual snorers are also more likely to Some medications such as felbamate, have headaches, suggesting the envi- zonisamide, or lamotrigine at high ronmental disturbance of sleep makes doses may cause insomnia. At lower headaches more likely.10 Also, 15% doses, lamotrigine and levetiracetam to 60% of patients with OSA report appear to have little overall effect on headaches, and these individuals are sleep. The overall downstream influ- more likely to develop morning head- ence of these medications on sleep ache, migraine, chronic headache, and and, possibly, on the epileptic focus tension-type headaches.10,13 Yet, treat- during sleep, still needs to be stud- ment of sleep apnea with continuous ied. Preliminary work suggests that positive airway pressure (CPAP) ap- chronopharmacology, adjusting so pears to improve headache frequency that sedating medications have higher and intensity.10,14 The interaction of doses at night, may improve seizure headaches, sleep, and epilepsy is illus- response and lower incidence of trated in Case 10-1. side effects.6 Some headache types emerge from specific stages of sleep (Table 10-2), SLEEP AND HEADACHES indicating sleep may set the neurochem- Headaches, similar to epileptic seizures, ical stage to initiate the headache.14 share a complex bidirectional relation- Cluster headaches typically emerge ship with sleep. Although both head- during REM sleep. Migraine headaches aches and sleep issues may be common that awaken a patient from sleep are and occur in the same patient, the more likely to be associated with vivid relationship of sleep to headaches ap- dreaming, suggesting they may arise pears to be more than coincidental. during REM sleep; however, further Sleep disruption can predispose, pro- studies are needed. Hypnic headaches voke, and perpetuate headache issues, (sometimes called alarm clock head- whereas sleep may also improve headaches) abruptly awaken patients after aches. In general, sleep deprivation and 1 to 3 hours of sleep and may respond excessive sleep increase headaches in to caffeine or, if frequent, treat- both children and adults.10 For patients ment with lithium. Chronic paroxysmal predisposed to headaches, the link to hemicrania also may awaken patients

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 10-1 A 27-year-old woman with static encephalopathy and focal-onset seizures presented with an 8-month progressive increase in her seizures. The patient previously had averaged approximately one seizure every 6 months, which had recently increased to two seizures per month. The intensity and duration of the seizures also appeared to have increased. The patient was being treated with lamotrigine 500 mg/d and previously had experienced no side effects. On presentation, she reported morning headaches, and the family noted that the patient fell asleep in the afternoon at the workshop where she spent most of her days. In review of her other symptoms, the family noted that the patient had had a 9 kg (20 lb) weight gain over the last 2 years, and the patient had begun snoring at night. The patient had an elevated Epworth Sleepiness Scale score of 11. An overnight sleep study revealed moderate obstructive sleep apnea with an apnea-hypopnea index of 17 per hour and events that had oxygen desaturation to 85%. Although initially the patient had difficulty adjusting to continuous positive airway pressure (CPAP), the patient and family incorporated positive behavior modification techniques that resulted in the patient wearing the CPAP on a nightly basis. After 3 months of therapy, the patient had only one seizure, and the daytime sleepiness and morning headaches had resolved. Comment. Sleep difficulties are a common aggravator of both epileptic seizures and headaches. This case demonstrates a patient with both increasing seizures and the development of headaches. However, either of these symptoms should be a clue to the clinician to ask about sleep issues. This case also demonstrates how the treatment of sleep issues such as obstructive sleep apnea may improve underlying neurologic conditions such as epilepsy or headaches. suddenly from sleep with abrupt fect long-term AD risk is that sleep, clawing pain, and these events respond particularly non-REM sleep, decreases well to indomethacin.14 Despite the amyloid-" through decreased produc- current lack of pathophysiologic un- tion and increased glymphatic clear- derstanding, both the mechanisms for ance.16,17 Therefore, sleep disruption sleep and headache generation share is predicted to increase amyloid-" some of the same hypothalamic and levels and, over time, increase risk of brainstem circuitry, and improvement insoluble amyloid plaque formation, in sleep offers a unique pathway to the first known step in AD pathogenesis. improve headache care. Sleep-wake disturbances bother- some to caregivers are present in SLEEP DISTURBANCES IN approximately 40% of community- ALZHEIMER DISEASE dwelling patients with symptomatic Sleep-wake and circadian disturbances AD18 and occur around the clock. start early in AD and increase in preva- While typically a circadian phase ad- lence and severity as AD progresses. vance occurs with aging, AD is associ- Even at the earliest presymptomatic or ated with a circadian phase delay.19 preclinical stage of AD, a bidirectional This phase delay probably contributes association exists between sleep distur- to sundowning (ie, restlessness, con- bance and AD pathology.15 Acandidate fusion, and agitation in the evening) mechanism by which sleep may af- that is difficult to treat and creates

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TABLE 10-2 Sleep-Related Headaches

Possible Sleep Headache Type Pain Description Association Treatment Cluster headache Short, excruciating, May occur near rapid Oxygen, triptans, lancinating pain behind eye movement verapamil, valproate, one eye with autonomic (REM) sleep lithium features such as red conjunctiva, dilated pupil, swelling around the eye, rhinorrhea, or ptosis; each episode lasts 15Y180 minutes Hypnic headache No autonomic symptoms, Awaken patient suddenly Caffeine, lithium typically short duration but from sleep at similar time lasts for 15Y180 minutes each night, typically after waking at 1:00 AM to 3:00 AM Paroxysmal Unilateral, severe, throbbing Can occur out of sleep Indomethacin hemicrania clawlike boring on the side and last 2Y45 minutes of the head, accompanied by autonomic symptoms Sleep apnea headache Bilateral pressing quality Present upon awakening, Positive airway pressure resolves in approximately 30 minutes

KEY POINTS substantial caregiver distress. Insom- measures specifically addressing sleep h Common sleep-wake nia at night may lead to wandering and circadian disturbances under neu- disturbances in and subsequent risk of falls or injury ropsychiatric symptom assessment, as Alzheimer disease and therefore is a frequent reason for well as a part of depressive symptom include nighttime institutionalization. During the day- screening.23 Additionally, given the insomnia, evening time, patients with AD may have growing literature on the effect of sundowning, and daytime sleepiness. excessive sleepiness, preventing en- sleep-wake disturbances in AD, sleep- Nighttime wandering gagement in social events and ther- wake functioning should be included raises safety concerns apies, while increasing the risk of as part of assessing safety/driving risks and increases caregiver driving accidents. and caregiver education. Unfortunately, burden and, therefore, OSA is particularly common in AD, is no specific treatments exist for sleep is a common reason for present in 40% of community-dwelling disorders in AD. Certainly, OSA should institutionalization. patients with AD, is present in up to be considered and treated if any symp- h Obstructive sleep apnea 70% of those with AD in the institution- toms are present. Typical hypnotic medi- 20,21 is very common in alized setting, and may contribute cations for insomnia may increase the patients with Alzheimer to cognitive symptoms. Since treat- risk of falls and injuries and should be disease, and treatment ment of OSA may be helpful in ame- used judiciously. Trazodone at low may improve cognitive liorating cognitive decline in AD,22 doses may improve total sleep time; symptoms. symptoms such as snoring, daytime otherwise, medications (including mel- sleepiness, or witnessed apneas should atonin) and light therapy have not been prompt evaluation for OSA. showntobeeffectiveinAD.24,25 Behav- The American Academy of Neurology ioral and pharmacologic treatments for (AAN) Dementia Measures Work Group sleep-wake disorders in dementia are defined dementia management quality under active investigation.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SLEEP-WAKE DISORDERS IN KEY POINTS sleep fragmentation, is the most com- h Sleep disorders affect PARKINSON DISEASE mon type of insomnia in PD. Up to the majority of patients PD is the second most common neuro- 80% of patients report sleep fragmen- with Parkinson disease. degenerative disorder. Disorders of tation and early morning awakenings. Sleep dysfunction in sleep and alertness affect most patients The etiology of sleep fragmentation in Parkinson disease is un- throughout the course of PD. Despite PD encompasses the overnight emer- derdiagnosed by health this, sleep disorders remain under- gence of motor PD symptoms, effects professionals reported by patients and underrecog- of dopaminergic medications on and underreported nized by health care professionals. All sleep, coexistence of other primary by patients. categories of sleep disorders are asso- sleep and psychiatric disorders, auto- h Sleep fragmentation is ciated with PD, and many have unique nomic dysfunction, and the influence the most common aspects when present in PD that likely of the primary neurodegenerative pro- sleep disturbance in reflect the interaction of PD-specific cess on sleep-wake regulatory centers Parkinson disease. neurodegeneration with mechanisms (Case 10-2).27 h The Parkinson Disease regulating sleep and alertness.26 Two scales have been developed to Sleep Scale and the assess sleep problems in PD, namely Scales for Outcomes in Insomnia the Parkinson Disease Sleep Scale and Parkinson Disease Sleep Insomnia is the most common sleep the Scales for Outcomes in PD Sleep Scale are specific to disorder in PD. Sleep maintenance Scale (SCOPA-S) scale.28 These scales Parkinson disease and are useful in assessing insomnia, frequently referred to as complement the clinical sleep history, sleep in patients with the disease. Case 10-2 A 69-year-old man presented with his wife for follow-up of his Parkinson disease (PD). His daytime motor symptoms of PD were well managed with carbidopa/levodopa 25 mg/100 mg 2 tablets 3 times a day and amantadine 100 mg 3 times a day. He endorsed prominent fatigue. Since his last office visit, his wife found him more withdrawn and unhappy. He also reported difficulties with sleep. He fell asleep without problems, but kept waking up every 2 hours thereafter. Sometimes, this was caused by a need to urinate, which had increased over the past 6 to 9 months. He also endorsed difficulties with turning in bed because of overnight stiffness. Since the last office visit, he had begun to wake up at 4:30 AM and was unable to fall back to sleep. Comment. Insomnia is common in PD. This patient had fragmented sleep and early morning awakenings. The case illustrates the multifactorial etiology of insomnia associated with PD. It appeared that this patient had developed a depressed mood since the last office visit. He also had an emergence of overnight motor symptoms of PD along with manifestations of autonomic dysfunction (nocturia), both of which can exacerbate poor sleep. Finally, he took amantadine at bedtime, which may have caused fragmented sleep because of its alerting properties. Treatment of depression along with the addition of long-acting carbidopa/levodopa at bedtime may improve mood and control overnight PD symptoms, which will likely improve sleep. A consultation with a urologist and subsequent treatment with a urodynamic agent may improve nocturia and reduce overnight awakenings. Finally, moving the bedtime dose of amantadine earlier in the day may improve sleep continuity. The possibility of comorbid sleep apnea and need for polysomnography may also be considered in this case, since untreated sleep-disordered breathing may occasionally present with sleep maintenance insomnia and excessive arousal, rather than predominant daytime sleepiness or symptoms of disruptive snoring.

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KEY POINTS h Dopaminergic which should emphasize factors spe- and PD duration or medication regi- medications frequently cific to PD. A thorough review of the men. Sleep-disordered breathing does cause excessive daytime medication regimen is needed. Opti- not correlate well with self-reported and sleepiness, where the mization of overnight PD symptoms, objective measures of sleepiness in PD. major predictive factor frequently with extended release levo- The severity of sleep-disordered breath- for excessive daytime dopa, may be beneficial for sleep. ing and mean overnight oxygen satura- sleepiness is not the Management of urinary dysfunction tion levels correlate with PD severity. specific type of or nocturia with urodynamic agents Nasal positive airway pressure (nPAP) dopaminergic agent, should be considered. Overnight hal- remains the main treatment of sleep- but rather the lucinations and confusion, especially in disordered breathing in PD. Adaptive total dose of patients with PD with cognitive impair- servo-ventilation may be the preferred dopaminergic therapy. ment, should not be overlooked, as type of positive airway pressure (PAP) in h Excessive daytime they pose significant challenges to patients with PD with predominant sleepiness and sleep overnight sleep. central apneas. Selection of an appropri- attacks pose significant Treatment of insomnia associated ate nPAP mask is very important as it safety issues for patients with PD encompasses behavioral and may determine the success of nPAP. In with Parkinson disease. Patients who experience pharmacologic interventions. Proper cases where nPAP is not tolerated, non- sleep attacks should be sleep hygiene should be implemented. PAP treatment modalities, such as a advised not to drive Classic behavioral approaches such fitted dental oral appliance or surgical until the issue is resolved. as stimulus control and sleep restric- interventions, may be considered. Im- tion have not been studied in PD, provements in overnight chest wall but certainly should be considered rigidity with modification of PD regimen in management. may also improve respiratory function and sleep-disordered breathing. Sleep-Disordered Breathing Sleep-disordered breathing has not Excessive Daytime Sleepiness been extensively studied in the PD Excessive daytime sleepiness affects population. Initial reports of irregular up to 50% of patients with PD.31 Male respiratory patterns with nocturnal gender, duration, and severity of PD worsening and central hypoventilation have been associated with excessive come from patients with postencepha- daytime sleepiness. Excessive daytime litic parkinsonism. Although sleep- sleepiness in PD has been associated disordered breathing remains common with the unexpected sudden onset of in PD, there is a similar prevalence of sleep, or ‘‘sleep attacks,’’ that pose sleep-disordered breathing in PD com- important safety implications, as epi- pared with the general population.29,30 sodes of falling asleep at the wheel While OSA is the most common have been reported in up to 23% of type of sleep-disordered breathing in patients with PD.32 The etiology of the general population, obstructive, excessive daytime sleepiness encom- central, and mixed apneas may be passes the primary neurodegenerative equally represented in PD. Obesity, a process, complex medication regi- strong predictor of sleep-disordered mens, age-related changes in the sleep breathing in the general population, is architecture, and coexistent sleep dis- not predictive of this disorder in PD, turbances. The loss of hypocretin/ since most patients with PD with orexin has been reported in PD and sleep-disordered breathing have nor- is likely an important culprit of ex- mal body mass indices. No clear cessive daytime sleepiness.33 Dopami- relationship exists between the preva- nergic medications frequently cause lence of sleep-disordered breathing excessive daytime sleepiness, where

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS the major predictive factor for exces- in patients who experience falls, h Rapid eye movement sive daytime sleepiness is not the higher disease severity, greater motor sleep behavior specific type of dopaminergic agent, fluctuations, and an increased levo- disorder frequently 35 but rather the total dose of dopami- dopa dose. The presence of RBD pre- precedes the onset of nergic therapy. dicts greater cognitive decline in PD. cardinal diagnostic Treatment of excessive daytime Prospective studies have revealed features of Parkinson sleepiness in patients with PD is phenoconversion rates of idiopathic disease and other challenging. Patient education about RBD to PD in approximately 75% to !-synucleinopathies. healthy sleep hygiene and timely diag- 90% of patients 10 to 14 years follow- h Rapid eye movement Y nosis of a coexistent sleep disorder ing RBD diagnosis.36 38 The most com- sleep behavior is essential. Soporific medications monly used medications to control disorder is present in should be minimized, and those with RBD attacks are melatonin and clonaze- approximately one-third activating properties (eg, selegiline or pam. Melatonin should be the first-line to one-half of patients amantadine) should be given earlier in therapy in patients with PD who have with Parkinson disease the day. The dose of dopaminergic RBD since it has fewer sedating prop- and is more prevalent among patients with an medications may need to be reduced. erties compared with clonazepam. akinetic/rigid phenotype Patients who experience sleep attacks and in patients who Restless Legs Syndrome should be advised not to drive until experience falls, higher the issue is resolved. Stimulants have For a full discussion concerning the disease severity, been used for the treatment of exces- diagnosis and treatment of restless greater motor sive daytime sleepiness with variable legs syndrome (RLS), refer to the fluctuations, and an success, and because of their adverse article ‘‘Restless Legs Syndrome and increased levodopa dose. effects, are rarely used in PD. Modafinil Sleep-Related Movement Disorders’’ h Prospective studies 39 has been evaluated for the treatment of by Lynn Marie Trotti, MD, MSc, in have revealed excessive daytime sleepiness in PD, and this issue of Continuum. RLS appears phenoconversion rates while some trials demonstrated im- to be more common in PD than in of idiopathic rapid eye provement in excessive daytime sleep- the general population and affects ap- movement sleep behavior iness with 100 mg/d to 200 mg/d, others proximately 20% of patients with disorder to Parkinson did not find any benefit. Melatonin may PD. Greater severity of PD, coexistent disease in approximately be beneficial in improving sleep quality depression, and reduced serum iron 75% to 90% of patients and reducing excessive daytime sleepi- binding capacity are risk factors for 10 to 14 years following diagnosis of rapid eye ness in PD. RLS in PD. Although both PD and RLS movement sleep respond favorably to dopaminergic behavior disorder. Rapid Eye Movement Sleep medications, no pathologic similarities h Behavior Disorder exist between these two disorders. Restless legs syndrome appears to be more REM sleep behavior disorder (RBD) Diagnosis of RLS in PD may be common in Parkinson frequently precedes the onset of car- challenging since several symptoms of disease than in the dinal diagnostic features of PD and PD, such as akathisia, overnight motor general population and " other -synucleinopathies. (For more symptoms, and dystonic symptoms, affects approximately 40 information on RBD, refer to the may mimic RLS. Furthermore, RLS 20% of patients with article ‘‘Rapid Eye Movement Sleep may fluctuate similarly to PD symp- Parkinson disease. Behavior Disorder and Other Rapid toms, and both disorders are treated Greater severity of Eye Movement Sleep Parasomnias’’ by with similar medications. The most Parkinson disease, Birgit Ho¨gl, MD, and Alex Iranzo, commonly used medications for the coexistent depression, MD,34 in this issue of Continuum.) treatment of RLS are dopamine ago- and reduced serum iron RBD is present in approximately one- nists, anticonvulsants, clonazepam, binding capacity are third to one-half of patients with PD and opioids. Levodopa for RLS treat- risk factors for restless legs syndrome in and is more prevalent among patients ment in patients with PD should be Parkinson disease. with an akinetic/rigid phenotype and avoided because of risks of rebound

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and augmentation, although most pa- disorders, most commonly hypoventi- tients with PD will continue to require lation due to restrictive thoracic disease usual doses of levodopa for their from weakness of respiratory muscula- motor symptom management. Iron ture, are reviewed in Table 10-3.41 A supplementation should be consid- common and illustrative disease is ered if ferritin levels are low. Medi- ALS, which is an incurable disease cations known to exacerbate RLS such characterized by progressive degenera- as dopamine blockers and anticholin- tion of the upper and lower motor ergic and antihistaminic agents should neurons. Survival is approximately 3 to be discontinued if possible. 5 years, with death usually due to respiratory failure. Lying flat places SLEEP COMORBIDITIES IN the diaphragm at a mechanical disad- AMYOTROPHIC LATERAL vantage, so hypoventilation due to SCLEROSIS AND restrictive thoracic disease in ALS often NEUROMUSCULAR DISORDERS presents as orthopnea at night, prior to The wide variety of neuromuscular daytime respiratory symptoms. Morn- disorders associated with various sleep ing headaches, daytime sleepiness, and

TABLE 10-3 Sleep Disorders in Neuromuscular Diseases

Neuromuscular Disorder Common Sleep Comorbidities Notes Amyotrophic lateral sclerosis Hypoventilation, obstructive Noninvasive ventilation improves sleep apnea survival and quality of life Duchenne muscular dystrophy Hypoventilation Both fixed restrictive and functional restrictive defects, often require tracheostomy because of 24 hour/d ventilation Myotonic dystrophy Obstructive sleep apnea, Frequent central apneas in response central sleep apnea, hypersomnia to positive airway pressure treatment, low hypocretin/orexin levels in CSF Inflammatory myopathies Obstructive sleep apnea, Frequently asymptomatic, so screening hypoventilation is essential; dermatomyositis most commonly affected; hypoventilation is related to diaphragmatic weakness Myasthenia gravis Obstructive sleep apnea Consider nasal continuous positive airway pressure therapy, alternative measures (position restriction, dental appliance, nasal expiratory positive airway pressure device) Restless legs syndrome Consider iron replacement therapy; dopamine agonist, gabapentin enacarbil, or pregabalin Acute inflammatory Hypoventilation, rapid eye May require intubation in acute phase; demyelinating movement (REM) REM sleep behavior disorder and polyradiculoneuropathy sleep behavior disorder other narcolepsylike symptoms may (Guillain-Barre´ syndrome) be related to low orexin levels in CSF Charcot-Marie-Tooth disease Restless legs syndrome Treatment strategy same as idiopathic restless legs syndrome CSF = cerebrospinal fluid.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS cognitive dysfunction are also common The most effective treatment for h Pulse oximetry is symptoms of hypoventilation. Further- sleep-related hypoventilation in ALS is incompletely sensitive more, because of weakness of oropha- nocturnal ventilation. Both invasive for hypoventilation, and ryngeal musculature, patients with ALS (via tracheostomy) and noninvasive supplemental oxygen are at high risk of OSA, thus snoring, ventilation (NIV) are available. NIV alone is contraindicated witnessed apneas, or frequent noctur- has been shown to prolong survival in patients with nal arousals may be presenting symp- by approximately 7 to 12 months,43 amyotrophic lateral toms. Other factors contribute to poor longer than the benefit from riluzole. sclerosis and sleep in ALS, such as central apneas, NIV extends quality of life for both neuromuscular bellows restless legs syndrome, muscle cramps, patient and caregiver and slows respi- failure, since oxygen discomfort from immobility, depres- ratory decline.43,44 The exception is may worsen carbon dioxide retention sion, and ALS-associated dementia. bulbar-predominant ALS, in which no and lead to acute Therefore, evaluation for hypoventi- study has identified a survival benefit respiratory failure. lation and sleep disorders should be from NIV; yet, NIV improves sleep h part of comprehensive ALS care. quality in bulbar-predominant ALS.43 In addition to nocturnal pulse oximetry, erect Screening for hypoventilation is Therefore, NIV should be offered, and supine spirometry, frequently done in the clinic via spi- unless patients prefer invasive ventila- maximal inspiratory/ rometry, specifically using the forced tion, ‘‘at the earliest sign of nocturnal expiratory force, sniff vital capacity. However, forced vital hypoventilation or respiratory insuffi- nasal pressure, and capacity measured in the upright ciency,’’ according to the AAN practice arterial blood gases 42 position is not particularly sensitive, parameters. should be obtained to so measurement in both supine and NIV is a subset of PAP, and the assess for suspected upright positions may demonstrate ‘‘target’’ of PAP therapy can be pres- hypoventilation in decline with recumbency. Nocturnal sure or volume. Until recently, bilevel amyotrophic lateral sclerosis and other desaturations with SaO2 of less than PAP was commonly used for NIV. 90% for 1 or more cumulative minutes However, in cases of increased resis- neuromuscular diseases. are more sensitive than forced vital tance to air entry due to secretions or h Noninvasive ventilation capacity for detecting hypoventilation; edema during infection, bilevel PAP prolongs survival and however, pulse oximetry may miss will deliver a lower volume at the time maintains quality of life mild hypoventilation.42 Furthermore, patients most need ventilatory sup- in patients with adding supplemental oxygen to treat port. Therefore, volume-targeted ven- amyotrophic lateral sclerosis. Ventilation hypoxia in patients with neuromuscu- tilation modes are preferred in ALS, in usually starts with lar bellows failure is contraindicated, which respiratory infection risk is nocturnal treatment and since this may cause additional carbon high. Previously, volume-targeted NIV then expands to dioxide retention and lead to worsen- required nonvented masks, which daytime treatment as ing of symptoms or even acute respi- greatly limited the selection of masks. symptoms progress. ratory failure, as illustrated in Case 10-3. Recently, volume-assured pressure Rather, a full assessment for hypo- support has been introduced for use ventilation should include spirometry with vented masks, allowing for a in the erect and supine positions, greater variety of masks to be used lung volumes, maximal inspiratory and with NIV. In volume-assured pressure expiratory pressures (peak inspiratory/ support, a volume target is set, along expiratory forces), sniff nasal pres- with a range of pressures that the sure, and arterial blood gases.35 Poly- machine is permitted to use to reach somnography, ideally with transcutane- the set target; this theoretically al- ous PCO2 monitoring, may be indicated lows the lowest required pressure to for identifying sleep-related hypoventila- be used, possibly improving comfort tion (in which PCO2 increases more and compliance, although prospective than 10 mm Hg during sleep) and OSA. studies demonstrating therapeutic

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Case 10-3 A 75-year-old man presented with a 2-year history of frequent falls and clumsiness. He was diagnosed with amyotrophic lateral sclerosis and treated with 3 L/min oxygen based on hypoxemia on home oximetry. He was referred to sleep medicine for excessive daytime sleepiness. Sleep history revealed no snoring or witnessed apneas. He went to bed at 9:30 PM and woke frequently all night for no apparent reason. He used three pillows because of orthopnea, yet awakened with a headache daily at 7:00 AM. His wife described him sleeping ‘‘all day’’ for 1 to 2 hours at a time in a recliner; even when awake, he was unable to hold a conversation. His score on the Epworth Sleepiness Scale was elevated at 14 out of 24. Pulmonary function testing revealed a restrictive defect with forced vital capacity of 58% predicted, and arterial blood gas on room air showed severe hypercapnia with pH 7.40, PCO2 67 mm Hg, and PO2 59 mm Hg. Polysomnography demonstrated severe obstructive sleep apnea with an apnea-hypopnea index of 38 events per hour of sleep. Sleep-related hypoventilation was demonstrated through an elevation of PCO2 from 74 mm Hg to 85 mm Hg during sleep. The patient was titrated with volume-assured pressure support. At optimal settings, the patient’s obstructive sleep apnea was fully treated, PCO2 improved to 59 mm Hg, and there was no oxygen requirement. He was set up for nocturnal volume-assured pressure support at home with a full face mask. At follow-up 2 months later, his wife described him as ‘‘back to himself,’’ alert, and witty. He was able to sleep soundly all night with one pillow, and he awakened feeling refreshed without a headache. He no longer took any naps, and his score of the Epworth Sleepiness Scale normalized to 0 out of 24. Comment. This case illustrates the importance of treating underlying hypoventilation rather than merely treating hypoxemia with supplemental oxygen, which can worsen carbon dioxide retention and subsequent drowsiness and headaches. Additionally, obstructive sleep apnea may be present even in the absence of obvious symptoms in amyotrophic lateral sclerosis, and noninvasive ventilation should be titrated to treat obstructive sleep apnea in addition to providing ventilatory support.

equivalency and tolerability to bilevel also offers a good opportunity to test PAP (BiPAP) are needed. different mask models, since mask fit OSA is quite common in ALS. is exceptionally important for patients Standard NIV settings (tidal volume is with ALS who may ultimately need to determined by height) may be insuffi- use NIV masks 24 hours per day. cient to maintain a patent upper airway Initially, most patients with ALS in comorbid OSA. A recent study found require NIV only when sleeping. How- that untreated obstructive events ever, as ALS progresses, dyspnea, ac- shortened survival in ALS despite treat- cessory muscle use, or hypercapnia/ ment with standard NIV, and these hypoxemia will eventually also occur obstructive events were not detected during the daytime. Mouthpiece venti- by pulse oximetry.45 Therefore, in lation is useful for bridging patients comorbid OSA, polysomnography for between nocturnal and around-the- NIV titration is recommended to identify clock ventilation. With this mode, the settings optimal for treating hypoven- patient can ‘‘suck’’ on a strawlike tilation and OSA. Polysomnography or similar mouthpiece interface for

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. ventilation as needed. Eventually, pa- 1998;39(12):1309Y1316. doi:10.1111/ tients with ALS will require 24-hour j.1528-1157.1998.tb01329.x. ventilator support. Whether the venti- 6. Vaughn BV, Ali I. Sleep and epilepsy: opportunities for diagnosis and treatment. lator support modality is noninvasive Neurol Clin 2012;30(4):1249Y1274. or invasive, patients and caregivers doi:10.1016/j.ncl.2012.08.006. should be counseled well in advance 7. Byars AW, Byars KC, Johnson CS, et al. The of the progressive decline in respira- relationship between sleep problems and neuropsychological functioning in children tory function. As respiratory insuffi- with first recognized seizures. Epilepsy ciency progresses, an accompanying Behav 2008;13(4):607Y613. doi:10.1016/ issue is the inability to clear secretions j.yebeh.2008.07.009. from the upper airway, so prescription 8. Klobucnı´kova´ K, Carnicka´ Z, Wagnerova´ H, of cough assist and suctioning devices Siarnik P. Is nocturnal epilepsy cause of disturbed quality of sleep and elevated should also be considered in parallel daytime sleepiness? Neuro Endocrinol Lett to optimizing NIV PAP therapy to 2014;35(5):405Y410. ensure tolerability and adequate ven- 9. Malow BA, Fromes GA, Aldrich MS. tilatory support. Usefulness of polysomnography in epilepsy patients. Neurology 1997;48(5):1389Y1394. CONCLUSION doi:10.1212/WNL.48.5.1389. 10. Freedom T. Headaches and sleep disorders. Essentially all classes of neurologic Dis Mon 2015;61(6):240Y248. doi:10.1016/ diseases are associated with one or j.disamonth.2015.03.008. more sleep disorders. Identifying and 11. Walters AB, Hamer JD, Smitherman TA. treating sleep dysfunction can help Sleep disturbance and affective comorbidity among episodic migraineurs. Headache 2014; patients remarkably in terms of their 54(1):116Y124. doi:10.1111/head.12168. sleep-related symptoms and quality of 12. Calhoun AH, Ford S. Behavioral sleep life and may also have a beneficial modification may revert transformed effect on the underlying neurologic migraine to episodic migraine. Headache disease symptom severity. Assessment 2007;47(8):1178Y1183. doi:10.1111/ j.1526-4610.2007.00780.x. for sleep disturbances should be rou- 13. Chiu YC, Hu HY, Lee FP, Huang HM. tine in the care of patients with Tension-type headache associated with neurologic diseases. obstructive sleep apnea: a nationwide population-based study. J Headache Pain REFERENCES 2015;16:34Y40. doi:10.1186/s10194-015-0517-5. 1. Temkin O. The falling sickness: a history of 14. Singh NN, Sahota P. Sleep-related headache epilepsy from the Greeks to the beginnings and its management. Curr Treat Options of modern neurology. Baltimore, MD: Johns Neurol 2013;15(6):704Y722. doi:10.1007/ Hopkins University Press, 1994. s11940-013-0258-1. 2. Rajna P, Veres J. Correlations between 15. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathologyVa bidirectional night sleep duration and seizure frequency relationship. Nat Rev Neurol 2014;10(2): in temporal lobe epilepsy. Epilepsia Y 1993;34(3):574Y579. doi:10.1111/ 115 119. doi:10.1038/nrneurol.2013.269. j.1528-1157.1993.tb02598.x. 16. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. 3. Kumar P, Raju TR. Seizure susceptibility Science 2013;342(6156):373Y377. decreases with enhancement of rapid eye doi:10.1126/science. movement sleep. Brain Res 2001;922(2): 299Y304. doi:10.1016/S0006-8993(01)03174-2. 17. Bero AW, Yan P, Roh JH, et al. Neuronal activity regulates the regional vulnerability 4. Minecan D, Natarajan A, Marzec M, Malow to amyloid-$ deposition. Nature Neurosci B. Relationship of epileptic seizures to sleep 2011;14(6):750Y756. doi:10.1038/nn.2801. stage and sleep depth. Sleep 2002;25(8): 18. McCurry SM, Logsdon RG, Teri L, et al. Y 899 904. Characteristics of sleep disturbance in 5. Malow BA, Lin X, Kushwaha R, Aldrich MS. community-dwelling Alzheimer’s disease Interictal spiking increases with sleep depth patients. J Geriatr Psychiatry Neurol in temporal lobe epilepsy. Epilepsia 1999;12(2):53Y59.

Continuum (Minneap Minn) 2017;23(4):1117–1131 ContinuumJournal.com 1129

19. Harper DG, Volicer L, Stopa EG, et al. 31. Breen DP, Williams-Gray CH, Mason SL, Disturbance of endogenous circadian et al. Excessive daytime sleepiness and rhythm in aging and Alzheimer disease. its risk factors in incident Parkinson’s Am J Geriatr Psychiatry 2005;13(5):359Y368. disease. J Neurol Neurosurg Psychiatry doi:10.1097/00019442-200505000-00004. 2013;84(2):233Y234. doi:10.1136/ jnnp-2012-304097. 20. Reynolds CF, Kupfer DJ, Taska LS, et al. Sleep apnea in Alzheimer’s dementia: correlation 32. Ondo WG, Dat Vuong K, Khan H, et al. with mental deterioration. J Clin Psychiatry Daytime sleepiness and other sleep disorders 1985;46(7):257Y261. in Parkinson’s disease. Neurology 2001;57(8):1392Y1396. doi:10.1212/ 21. Ancoli-Israel S, Klauber MR, Butters N, et al. Dementia in institutionalized elderly: WNL.57.8.1392. relation to sleep apnea. J Am Geriatr Soc 33. Fronczek R, Overeem S, Lee SY, et al. Y 1991;39(3):258 263. doi:10.1111/ Hypocretin (orexin) loss and sleep j.1532-5415.1991.tb01647.x. disturbances in Parkinson’s Disease. Brain 22. Troussie` re AC, Charley CM, Salleron J, et al. 2008;131(pt 1):e88. Treatment of sleep apnoea syndrome 34. Ho¨ gl B, Iranzo A. Rapid eye movement decreases cognitive decline in patients with sleep behavior disorder and other rapid eye Alzheimer’s disease. J Neurol Neurosurg movement sleep parasomnias. Continuum Y Psychiatry 2014;85(12):1405 1408. (Minneap Minn) 2017;23(4 Sleep doi:10.1136/jnnp-2013-307544. Neurology):1017Y1034. 23. Odenheimer G, Borson S, Sanders AE, et al. 35. Postuma RB, Gagnon JF, Vendette M, et al. Quality improvement in neurology: REM sleep behaviour disorder in Parkinson’s dementia management quality measures. disease is associated with specific motor Y Neurology 2013;81(17):1545 1549. features. J Neurol Neurosurg Psychiatry doi:10.1212/WNL.0b013e3182a956bf. 2008;79(10):1117Y1121. doi:10.1136/ 24. McCleery J, Cohen DA, Sharpley AL. jnnp.2008.149195. Pharmacotherapies for sleep disturbances in 36. Iranzo A, Santamaria J, Tolosa E. Idiopathic Alzheimer’s disease. Cochrane Database Syst rapid eye movement sleep behaviour Rev 2014;0033:CD009178. doi:10.1002/ disorder: diagnosis, management, and the 14651858.CD009178.pub2. need for neuroprotective interventions. 25. Forbes D, Blake CM, Thiessen EJ, et al. Light Lancet Neurol 2016;15(4):405Y419. therapy for improving cognition, activities doi:10.1016/S1474-4422(16)00057-0. of daily living, sleep, challenging behaviour, 37. Iranzo A, Ferna´ ndez-Arcos A, Tolosa E, and psychiatric disturbances in dementia. et al. Neurodegenerative disorder risk in Cochrane Database Syst Rev 2014;2:CD003946. idiopathic REM sleep behavior disorder: study doi:10.1002/14651858.CD003946.pub4. in 174 patients. PLoS One 2014;9(2):e89741. 26. Videnovic A, Golombek D. Circadian and doi:10.1371/journal.pone.0089741. sleep disorders in Parkinson’s disease. Exp 38. Schenck CH, Boeve BF, Mahowald MW. Y Neurol 2013;243:45 56. doi:10.1016/ Delayed emergence of a parkinsonian j.expneurol.2012.08.018. disorder or dementia in 81% of older men 27. Schrempf W, Brandt MD, Storch A, initially diagnosed with idiopathic rapid eye Reichmann H. Sleep disorders in Parkinson’s movement sleep behavior disorder: a disease. J Parkinsons Dis 2014;4(2):211Y221. 16-year update on a previously reported doi:10.3233/JPD-130301. series. Sleep Med 2013;14(8):744Y748. doi:10.1016/j.sleep.2012.10.009. 28. HPgl B, Arnulf I, Comella C, et al. Scales to assess sleep impairment in Parkinson’s 39. Trotti LM. Restless legs syndrome and disease: critique and recommendations. Mov sleep-related movement disorders. Disord 2010;25(16):2704Y2716. doi:10.1002/ Continuum (Minneap Minn) 2017;23(4 Sleep mds.23190. Neurology):1005Y1016. 29. Cochen De Cock V, Arnulf I. REM sleep 40. Rijsman RM, Schoolderman LF, Rundervoort behavior disorders and their characteristics RS, Louter M. Restless legs syndrome in in Parkinson’s disease [in French]. Revue Parkinson’s disease. Parkinsonism Relat Neurologique 2008;164(8-9):683Y691. Disord 2014;20(suppl 1):S5YS9. doi:10.1016/ doi:10.1016/j.neurol.2007.10.008. S1353-8020(13)70004-X.

30. Trotti LM, Bliwise DL. No increased risk of 41. Fermin AM, Afzal U, Culebras A. Sleep in obstructive sleep apnea in Parkinson’s neuromuscular diseases. Sleep Med Clin disease. Mov Disord 2010;25(13):2246Y2249. 2016;11:53Y64. doi:10.1016/ doi:10.1002/mds.23231. j.jsmc.2015.10.005.

1130 ContinuumJournal.com August 2017

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 42. Miller RG, Jackson CE, Kasarskis EJ, et al. 2006;5(2):140Y147. doi:10.1016/ Practice parameter update: the care of the S1474-4422(05)70326-4. patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies 44. Lo Coco D, Marchese S, Pesco MC, (an evidence-based review). Report of the et al. Noninvasive positive-pressure Quality Standards Subcommittee of the ventilation in ALS: Predictors of tolerance Y American Academy of Neurology. Neurology and survival. Neurology 2006;67(5):761 765. 2009;73(15):1218Y1226. doi:10.1212/ doi:10.1212/01.wnl.0000227785.73714.64. WNL.0b013e3181bc0141. 45. Georges M, Attali V, Golmard JL, et al. 43. Bourke SC, Tomlinson M, Williams TL, et al. Reduced survival in patients with ALS Effects of non-invasive ventilation on with upper airway obstructive events on survival and quality of life in patients non-invasive ventilation. J Neurol Neurosurg with amyotrophic lateral sclerosis: a Psychiatry 2016;87(10):1045Y1050. randomised controlled trial. Lancet Neurol doi:10.1136/jnnp-2015-312606.

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