Review Article

Address correspondence to Dr Nathaniel F. Watson, Harborview Medical Center, and Comorbid UW Medicine Sleep Center, 325 Ninth Ave, Box 359803, Seattle, WA, 98104, Neurologic Disorders [email protected]. Relationship Disclosure: Nathaniel F. Watson, MD, MSc; Mari Viola-Saltzman, DO Dr Watson serves on the Board of Directors for the American Academy of and the American ABSTRACT Sleep Medicine Foundation. Dr Viola-Saltzman reports no Purpose of Review: An understanding of the impact of sleep on neurologic disclosure. disorders, and the impact of neurologic disorders on sleep, provides fresh opportunities Unlabeled Use of for neurologists to improve the quality of life and functioning of their patients. Products/Investigational Recent Findings: Sleep-disordered (SDB) is a risk factor for cerebrovascular Use Disclosure: Drs Watson and Viola-Saltzman report no and should be considered in all TIA and patients. Sleep disorders can disclosures. amplify nociception and worsen disorders; and some , including * 2013, American Academy those related to SDB and hypnic headache, are sleep specific. REM sleep behavior of . disorder may be an early sign of neurodegenerative disease. Focal lesions of almost any etiology (eg, and CNS malignancies) in the hypothalamus, basal forebrain, or brainstem may result in sleep disturbance, sleepiness, and . Sleep-related hypoventilation and fatigue are common in neuromuscular disease. SDB and are mutually facilitatory, and poor sleep can exacerbate epilepsy. Summary: Continued surveillance for sleep disorders by neurologists is rewarded by new treatment avenues in their patients with the possibility of improved clinical outcomes.

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INTRODUCTION increases incident stroke risk.2Y6 Even Sleep medicine is neurology; all sleep mild SDB is associated with increased 5 disorders emanate from or involve the incident stroke and increased risk of 6 central or peripheral . composite stroke, TIA, or death. The Even sleep-disordered breathing (SDB), reverse is also true: incident cardiovas- considered by many a pulmonary or cular disease is associated with worsen- 7 otolaryngologic disorder, is caused in ing of SDB over a 5-year period. large part by ineffective maintenance of Incident stroke in particular increases oropharyngeal muscle tone in sleep. The central SDB, which is common following intersection between sleep and neuro- stroke, and may represent silent brain logic disorders is broad and deep. Al- ischemia disturbing central respiratory Supplemental digital content: mechanisms.8 Table 8-1 presents a syn- Videos accompanying this ar- most every neurologic disorder affects ticle are cited in the text as or is affected by sleep. opsis of epidemiologic studies assessing Supplemental Digital Content. incident stroke in patients with SDB. Videos may be accessed by clicking on links provided in Stroke timing favors a role for SDB. the HTML, PDF, and iPad AND SLEEP-DISORDERED Awakening increases sympathetic versions of this article; the BREATHING URLs are provided in the print nervous system activity and the renin- version. Video legends begin Multiple well-adjusted, cross-sectional angiotensin-aldosterone axis, causing a on page 165. studies show a dose-response relation- sharp morning rise in arterial blood ship between sleep-disordered breath- pressure and . Both ischemic ing (SDB) severity and odds of prevalent and hemorrhagic stroke have a peak stroke.1,2 Longitudinal studies also dem- incidence in the morning hours, with onstrate that increased SDB severity ischemic stroke occurring about the time

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 8-1 Synopsis of Studies Assessing Incident Stroke in Patients With Sleep-Disordered Breathing

Number Time of Events Fully Adjusted Followed () Odds Ratio or Study N = (Years) Observed Hazard Ratio P Value Comments Arzt2 1189 4 21 OR: 3.08 .120 Unadjusted OR: 4.31 (95% CI; 0.74Y12.81) (1.31Y14.15), P=.02 Munoz3 394 6 20 HR: 2.52 .040 HR presented for subjects (95% CI; 1.04Y6.01) with severe obstructive (apnea- index [AHI] Q30 events/h) Redline4 5422 ~8 193 HR: 2.86 .016 Incident stroke was not (95% CI; 1.10Y7.40) associated with AHI quartiles in women HR presented for highest AHI quartile (919 events/h); P value is for trend Valham5 392 10 47 HR: 3.56 .011 HR presented for subjects (95% CI; 1.56Y8.16) with moderate to severe (AHI Q15 events/h); P value is for trend Yaggi6 1022 ~3 88 HR: 1.97 .010 Outcome was incident (95% CI; 1.12Y3.48) stroke and death OR = odds ratio; CI = confidence interval; HR = hazard ratio. mostpeoplearewakinguptostarttheir indices and lower mean oxygen sat- day.9 Interestingly, none of the more uration levels. The presence of severe common vascular risk factors or other sleep apnea (apnea-hypopnea index etiologic factors for stroke (including [AHI] greater than 30 events/h) was patient demographics, vascular distribu- independently associated with wake-up tion, ischemic heart disease, previous stroke.11 , diabetes mellitus, During healthy nocturnal sleep, both hypertension, smoking, hyperlipidemia, systolic and diastolic blood pressures stroke severity and recurrence, stroke drop by 10% to 20% from respective subtype, and other clinical features) vary daytime mean levels. Some patients, in a statistically significant manner referred to as nondippers, have less than according to the clock time of stroke a 10% decline in blood pressure relative onset.10 The temporal pattern of stroke to respective daytime means. Nondip- points to the impact of circadian factors ping, over time, likely contributes to left on vascular tone, coagulative balance, ventricular hypertrophy, renal pathol- and blood pressure. Perhaps most com- ogy, and deleterious effects on brain pellingly, a case-control study compar- vasculature such as atheromatous nar- ing subjects with wake-up stroke to rowing or occlusion of larger cerebral those without wake-up stroke found vessels, thickening of cerebral arteries by the wake-up stroke group had higher lipohyalinosis, and increased blood co- apnea-hypopnea and obstructive apnea agulability. Nondipping blood pressure

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KEY POINTS h pattern is associated with stroke inde- by approximately 1.5 mm Hg to 2.5 Sleep-disordered 12 breathing is a term that pendent of sex and race. Stroke risk is mm Hg and diastolic blood pressure by 16,17 encompasses all increased by 80% for every 5 mm Hg 1.5 mm Hg to 2.0 mm Hg. In 13 breathing disturbances increase in sleep-time blood pressure. another two meta-analyses reporting in sleep, including Obstructive sleep apnea (OSA) is one of changes in blood pressure obtained by obstructive sleep apnea, the most common causes of nondip- ambulatory monitoring, CPAP use was central sleep apnea, ping nocturnal blood pressure. associated with an approximately 1.0 Cheyne-Stokes The effect of SDB on blood pressure mmHgto1.5mmHgreductionin respirations, and upper is not confined only to the sleep period. both 24-hour systolic and diastolic blood airway resistance Approximately 50% to 60% of patients pressure.18,19 In subgroup analyses, syndrome. with OSA are hypertensive, while about severe OSA (more than 30 events per h Sleep-disordered 30% to 40% of hypertensive patients hour), higher blood pressure levels, and breathing is an have OSA.14 Peppard and colleagues15 greater CPAP adherence were associ- independent risk factor performed a 4-year, population-based, ated with larger reductions in blood for stroke. prospective cohort study of OSA and pressure.16Y19 hypertension. After adjusting for multi- ple confounders, they found that even Additional Obstructive Sleep people with few episodes of apnea or Apnea–Related Factors That hypopnea (0.1 events/h to 4.9 events/h) Increase Stroke Risk at baseline had 42% greater odds of OSA increases systemic sympathetic having hypertension at follow-up than nervous system activity and atrial size people with no episodes. They also (through left ventricular hypertrophy found those with mild SDB (AHI of 5.0 and increased transmural pressure), events/h to 14.9 events/h) and those which increases the risk of atrial fibrilla- with more severe SDB (AHI of 15.0 or tion, a major stroke risk factor.20 In ad- more events/h) had approximately 2 and dition, cardioverted is 3 times, respectively, the odds of having more likely to recur in untreated versus hypertension at follow-up than those treated OSA patients.21 Sleep disrup- with no episodes of apnea or hypo- tion and chronic intermittent pnea.15 Resistant hypertension is defined in OSA increase oxidative stress and as blood pressure that requires four or vascular , which results in more antihypertensive medications. endothelial dysfunction characterized by Stunningly, 80% to 90% of these patients reduced vasodilatation and enhanced have OSA. Pathophysiologic mecha- vasoconstriction, including chronic pro- nisms include activation of the renin- thrombotic and procoagulant activity.22 angiotensin-aldosterone system by Apneas are associated with reduced intermittent hypoxia and aldosterone- cerebral perfusion and delayed cere- related fluid retention causing para- brovascular compensatory response to pharyngeal edema.14 Thus, OSA is a risk changes in blood pressure.23,24 CPAP factor for hypertension and a major risk therapy has beneficial effects on vas- factor for stroke. cular function and inflammatory and oxidative stress in these patients.25 OSA Treatment of Obstructive Sleep is associated with patent foramen ovale Apnea to Improve Blood Pressure (PFO), an important cause of crypto- In two meta-analyses reporting changes genic stroke. During an obstructive ap- in blood pressure levels, patients ran- nea, large intrathoracic pressure swings domized to continuous positive airway and hypoxic pulmonary vasoconstric- pressure (CPAP) therapy compared with tion act in concert to alter the interatrial controls reduced systolic blood pressure pressure balance in favor of right to left

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. PFO shunting,26 which may be pre- pliant group.31 Long-term CPAP treat- ventable with CPAP therapy.27 The ment in moderate to severe OSA and presence of sleep apnea, including the ischemic stroke is associated with a re- duration and severity of disease, is duction in excess risk of mortality.32 associated with carotid intima-media Treatment of OSA by CPAP in stroke thickness,28 some of which is reversi- patients undergoing rehabilitation im- ble with the application of CPAP ther- proved functional and motor, but not apy.29 SDB is also associated with neurocognitive, outcomes.33 Random- diabetes mellitus and insulin resist- ized controlled trials are ongoing with ance, with the strength of association in- the goal of determining whether CPAP creasing as a function of OSA severity.30 therapy for OSA can prevent incident The effect of CPAP therapy on glucose cardiovascular disease and death. metabolism in patients with OSA has yet to be established. Figure 8-1 dis- Sleep-Disordered Breathing plays the complicated risk-factor rela- Following Stroke tionship between SDB and stroke. Acutely poststroke, over two-thirds of 161 stroke patients had an AHI of more than Treatment of Sleep-Disordered 10 events/h. After 3 months, both the Breathing to Prevent Stroke AHI and central apnea index were signifi- In patients with previous cardiovascular cantly lower than in the acute phase, events and moderate to severe OSA, predominantly because of reductions those noncompliant with CPAP therapy in central apneas, since the obstructive had an increased incidence of new apnea index remained unchanged. Inter- ischemic stroke compared to the com- estingly, stroke location, type, or vascular

FIGURE 8-1 Interplay of risk factors for sleep-disordered breathing (SDB) and stroke. SDB influences stroke through shared risk factors, facilitation of traditional stroke risk factors, and physiology unique to SDB. The latter likely explains why SDB is associated with incident stroke after adjustment for many of these other risk factors.

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KEY POINTS h territory was not associated with SDB in Unfortunately, despite the strength of Sleep-disordered 34 breathing should be this study. This, along with the fact that the evidence, SDB is regularly unrecog- considered in all stroke SDB frequency and severity are the nized and undiagnosed in both primary 35 and TIA patients. same for stroke and TIA patients, care and neurology/stroke clinics across h Cervical is suggests that although stroke itself can the country. Considering what is at associated with reduced worsen SDB through effects on orophar- stake, evaluation for SDB is essential sleep quality and yngeal musculature and brainstem respi- to the workup of any TIA or stroke sleepiness, even when ratory centers, the SDB likely precedes patient. The identification and treat- compared to patients the vascular event in most cases. ment of SDB in these patients provides with other focal a tremendous opportunity for neurolo- movement disorders. Sleep Duration and Stroke gists and stroke specialists to mitigate Pathophysiology the adverse effects of cerebrovascular A recent study found both short and disease (Case 8-1).37 long sleep durations to be associated with stroke, independent of age, sex, MOVEMENT DISORDERS AND body mass index, physical activity, smok- SLEEP IMPAIRMENT ing, alcohol use, screen time (eg, time Sleep and movement disorders overlap in spent in front of TVs, computers, tablets, a number of important ways. This section smart phones), country of birth, marital focuses on the sleep-related ramifications status, education, and employment sta- of the , choreiform disorders, tus. Compared with a sleep duration of , and tics. Other sections of this 7 hours (referent), the multivariate odds article address other - ratio (OR) of stroke for various sleep related issues, including the relation- durations was as follows: less than 6 ship of sleep with Parkinson disease hours, OR = 1.54 (1.36Y1.75); 6 hours, (PD) and with Lewy bodies. OR = 1.25 (1.14Y1.38); 8 hours, OR = Sleep impairment and its secondary 1.08 (1.00Y1.17); and 9 hours or more, symptoms have substantial quality of life OR = 1.50 (1.38Y1.62).36 The exact ramifications for patients with dystonia. mechanism is unknown but likely re- Cervical dystonia is associated with re- lated to effects on metabolic, endo- duced sleep quality and sleepiness, even crine, and autonomic nervous systems. when compared to other focal move- Conclusions. SDB is an indepen- ment disorders.38 A number of poly- dent risk factor for stroke. It meets the somnographic abnormalities have been criteria of biological plausibility, predic- reported, including problems with sleep tiveness, dose-responsiveness, and pre- initiation and maintenance, reduced stroke measurability. SDB is associated sleep efficiency, abnormal or reduced with many known stroke risk factors, REM sleep, and changes in spindle including incident hypertension, endo- activity.39 Similar to other nonmotor thelial dysfunction, oxidative stress, dystonia symptoms, the etiology of vascular inflammation, prothrombotic sleep abnormalities includes primary ef- and procoagulant factors, , fects of dystonia and secondary effects diabetes, PFO, and carotid intima- of pain and medications (eg, benzodia- media thickness. Treatment of SDB zepines, anticholinergics). Some forms with CPAP improves many stroke risk of dystonia, including factors, including reducing hyperten- and Meige syndrome, may persist dur- sion and carotid intima-media thick- ing sleep, although frequency and se- ness, reversing right to left shunting in verity are often decreased. PFO, and reducing recurrence of atrial Sleep problems are present in nearly fibrillation following cardioversion. 90% of patients with Huntington disease

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 8-1 h Sleep disturbance is present in nearly 90% An obese 59-year-old hypertensive man presented to his primary care of patients with physician because of a transient episode of difficulty speaking 2 days earlier. Huntington disease, In the course of the examination, the physician found evidence for atrial with most rating it a fibrillation. Diagnostic testing included echocardiography significant for significantly important patent foramen ovale (PFO) with a positive bubble test indicating right to factor in overall health left shunting, and hypercholesterolemia. Carotid ultrasound was normal. impairment. The physician referred the patient to a cardiologist for cardioversion of his atrial fibrillation, and prescribed warfarin, metoprolol, and simvastatin. The patient’s atrial fibrillation was successfully cardioverted 4 weeks after warfarin therapy, and warfarin was switched to aspirin 4 weeks after cardioversion. Three weeks later, the patient presented to the emergency department aphasic and hemiparetic from a large left middle cerebral artery distribution stroke and was found to have recurrent atrial fibrillation. Comment. This obese older man with hypertension, atrial fibrillation, and PFO is at high risk for having sleep-disordered breathing (SDB). Because no evaluation and management of the SDB was done, the patient was at higher risk for recurrent atrial fibrillation following cardioversion and subsequent stroke. Although whether treatment of SDB with continuous reduces incident stroke is unknown, it is clear that untreated sleep apnea increases the risk of recurrence of atrial fibrillation following cardioversion. PFO is also associated with SDB, but atrial fibrillation is a more likely explanation for the stroke mechanism in this patient. Evaluation for SDB should be performed in TIA and stroke patients as part of their stroke workup.

(HD), with nearly two-thirds rating sleep which are increased in HD and may dysfunction as either very or moderately represent rather than periodic important factors contributing to overall limb movement disorder.41 HD is asso- health impairment.40 As HD progresses, ciated with brainstem atrophy, even non-REM (NREM) sleep stages N1 and before caudate atrophy and in one small N2 are increased, and NREM sleep stage study, REM sleep behavior disorder N3 and REM are decreased. In contrast (RBD) was observed in 12% of patients to other neurodegenerative , with HD.42 In general, chorea and patients with HD show a higher density decrease and may even dis- of sleep spindles compared to healthy appear during sleep,makingtheseun- control subjects. Actigraphy studies likely major sleep disrupters in HD, as show patients with HD have significantly opposed to dystonia, dementia, body more movements and increased activity pain, and , which more likely during sleep compared with controls. impair sleep in this disorder. Atrophy in With increasing HD severity, sleep the dorsolateral hypothalamus (site of latency increases, sleep maintenance hypocretin/orexin production) and ante- becomes more difficult, sleep efficiency rior ventral hypothalamus (site of the reduces, wakefulness after suprachiasmatic nucleus) may explain increases, circadian rhythmicity be- sleepiness and circadian and other sleep comes compromised, and sleepiness disruption in this disorder. ensues.41 SDB, , and restless When compared to age- and sex- legs syndrome are not more common in matched controls, patients with essential patients with HD, as opposed to peri- have poorer nocturnal sleep qual- odic limb movements of sleep (PLMS), ity but not increased daytime sleepiness.43

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KEY POINTS h Sleep is impaired in However, pain and fatigue scores were and diagnostic groups (eg, , clus- 20% to 50% of elevated among patients with essential ter, tension-type). Variations in circadian children and young tremor, suggesting many misconstrue timing of sleep and sleep duration out- adults with Tourette sleepiness as fatigue. RBD does not appear side typical norms (ie, 7 to 9 hours per syndrome. to be associated with . night) are common headache triggers. Al- h Obstructive sleep apnea Caregiver observations indicate sleep though sleep and headache associations is a common cause for problems in 20% to 50% of children and are diverse, sleep dysfunction influences headache upon young adults with Tourette syndrome. headache threshold through effects on 47 awakening, particularly Difficulties in falling and staying asleep, sleep regulatory processes. Relative to an if it dissipates during the separation anxiety in the evening, and age- and sex-matched chronic headacheY course of the day. were the most common free comparison group, headache pa- 44 h should be problems. Children with tic disorder tients slept significantly shorter durations considered as a potential and Tourette syndrome have objective (6.7 versus 7.0 hours), reported longer cause for headache sleep impairment indicated by reduced sleep latencies (31.4 versus 21.1 min- upon wakening. sleep efficiencies, prolonged sleep utes), and took longer to resume sleep h Patients with cluster latencies, and increased arousal indi- following nighttime awakening (28.5 44,45 48 headache have an ces. The disturbed sleep of children versus 14.6 minutes). eightfold increased with Tourette syndrome is accompa- Chronic morning headache occurs in risk of obstructive nied by increased short-lasting motor nearly 8% of the population, with sleep sleep apnea when activity in NREM sleep, which likely complaints more typical among those compared to age- and represents tic activity during sleep.44 with tension-type than migraine head- sex-matched controls. ache.49 Of migraine patients, 24% de- HEADACHE DISORDERS scribe headache onset during sleep or AND SLEEP upon awakening as opposed to 12% of Sleep and headache have a complicated tension-type headache patients.46 Head- interrelationship. Although a history of ache is more common among people headache upon awakening raises a con- with SDB than the general population, cern for a space-occupying CNS lesion, and habitual is more typical of this symptom is more likely to represent chronic daily headache than episodic SDB, especially in obese men with headache. Morning headache is over 3 tension-type headache pain that dissi- times more common in snorers and pates during the course of the day. In apneics compared to healthy controls. some instances, sleep improves head- Bruxism is another potential cause for ache, as exemplified by the typical pa- morning headache. In a study of over tient with migraine lying in a dark, quiet 1000 patients with migraine, sleep dis- room. In other instances, such as hypnic turbance and oversleeping were recog- headache, sleep and specific sleep stages nized as headache precipitants by 50% trigger the headache. Headache pain, or and 37% of patients, respectively, while pain of any kind, adversely affects sleep 85% reported sleeping as a means to architecture, duration, and quality; and relieve headache. Many reported occa- patients with sleep disorders report over sional sleep-onset (53%) and mainte- 4 times more headaches than healthy nance (61%) difficulties. Almost two- controls.46 thirds reported morning headaches.50 Sleep disorders such as insomnia, patients have an eight- SDB, sleep-related movement disor- fold increase in OSA compared to age- ders, and disorders and sex-matched controls, and a 24-fold are disproportionately observed in spe- increase when overweight or obese.51 cific headache patterns (eg, chronic Treatment of OSA has been shown to daily headache, awakening headache) improve cluster headache control.46

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS Hypnic headache is a rare primary h TABLE 8-2 Common Screening Hypnic headache is headache disorder in older adults char- Instruments sleep specific, occurring acterized by moderate, throbbing, bilat- relative to REM sleep at eral, or unilateral sleep-related headache b Sleepiness a consistent time of attacks with typical onset in REM sleep. Epworth Sleepiness Scale the night. Headache duration can be anywhere Stanford Sleepiness Scale h Epilepsy and Karolinska Sleepiness Scale from 15 minutes to 3 hours. In REM, sleep-disordered dorsal raphe and locus coeruleus activity b Sleep-Disordered Breathing breathing are mutually is absent and these areas, along with Berlin Questionnaire facilitatory, with higher the periaqueductal gray, are essential Multivariate Apnea Prediction rates of each disorder components of the human antinoci- Index observed in patients ceptive system. Hypnic headache may STOP-BANG questionnaire with the other disorder therefore represent REM-related mal- b Insomnia when compared to the function of these neuroanatomic re- Insomnia Severity Index general population. gions, although this may not be specific b Sleep Quality h One in five patients with since migraine and cluster headache Pittsburgh Sleep Quality Index epilepsy has onset also commonly occur in REM. exclusively during sleep. Because many patients with hypnic h Most sleep-related headache experience headache onset at disorders can contribute to difficulty in seizures occur out of a consistent time of night, areas involved managing seizures, and epilepsy can non-REM sleep, most in circadian rhythm generation, such as disrupt normal sleep, initiating or wor- often non-REM sleep the suprachiasmatic nucleus (SCN), also sening sleep disorders. Patients with stage N2. may be involved. The SCN has afferent epilepsy commonly report poor sleep and efferent connections with the peri- quality, increased nocturnal awakenings, aqueductal gray, further strengthening early morning awakenings, difficulty ini- this notion. , either at or tiating sleep, and excessive daytime following headache onset, is an effective sleepiness. Nineteen percent of general- treatment but concerns for sleeplessness ized seizures occur during sleep, as com- limit its use. Lithium, indomethacin, and pared to 51% of localization-related are also helpful in some pa- seizures. One in five patients with epi- tients, along with other headache med- lepsy has seizures exclusively during ications on a case-by-case basis.52 sleep. Examples of focal-onset epilepsy Because sleep and headache are so occurring predominantly during sleep tightly linked, diagnosing and treating include benign focal epilepsy with cen- comorbid sleep disorders afford an trotemporal spikes, and nocturnal fron- opportunity to improve the headache tal lobe epilepsy. Many patients have problem. The most likely sleep disorders ‘‘awakening epilepsy,’’ occurring within for headache causality are SDB, sleep 2 hours of waking; juvenile myoclonic deprivation, and circadian rhythm dis- epilepsy is a classic example. Table 8-3 turbances. A number of good screening provides a list of with a pre- instruments are available for clinical use dilection for occurrence out of sleep. to help identify headache patients that Most sleep-related seizures occur out might benefit from consultation with a of NREM sleep, with NREM sleep stage sleep medicine specialist (Table 8-2). N2 being the most common. This sleep stage likely facilitates focal spikes and EPILEPSY AND SLEEP epileptic activity through thalamocorti- Sleep disorders and epilepsy are fre- cal hypersynchrony, as represented by quently comorbid. The relationship be- characteristic sleep spindles and K com- tween the two can be reciprocal; sleep plexes. Hypersynchronous delta activity

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KEY POINT h syndrome (Table 8-4). These patients Nocturnal frontal lobe TABLE 8-3 Common epilepsy can be difficult Sleep-Related have brief stereotyped hyperkinetic or to distinguish from Epilepsies tonic motor seizures that occur in parasomnias, with clusters during sleep following sudden stereotypia, minimal b Nocturnal frontal lobe epilepsy arousals. Kicking and movement of legs, postevent confusion, arms, and trunk are seen. Patients b Nocturnal temporal lobe epilepsy and shorter duration typically maintain consciousness during providing clues that the b Benign focal epilepsy with the seizures, which usually last less than event was epileptic in centrotemporal spikes 60 seconds and are stereotyped in nature. b Juvenile nature. Seizures usually begin in child- b Continuous spike-wave hood and persist throughout life. The discharges during demonstrates an autosomal dominant inheritance pattern with an b Childhood epilepsy with occipital paroxysms approximate penetrance of 70%. Seiz- ures involve deep mesial frontal gener- b Generalized tonic-clonic ators and may lack ictal and interictal seizures upon awakening EEG correlates. For all these reasons, nocturnal frontal lobe epilepsy can be difficult to differentiate from NREM in NREM sleep stage N3 also facilitates parasomnias (Table 8-5)(Case 8-2).55 epileptiform activity. Nighttime interic- Historically, has tal activity is more suggestive of the been used to provoke epileptic-related location of the focus than day- EEG activity. Sleep itself may activate time interictal activity.53 Seizures are interictal activity in approximately one- least likely to occur out of REM sleep, third of patients with epilepsy and up to but when they do, they can provide the 90% of people with sleep-wakeYrelated most accurate seizure localization of any sleep stage. Seizures and epilepti- form abnormalities are typically ob- TABLE 8-4 Characteristics of served during sleep stage transitions Autosomal Dominant Nocturnal Frontal and unstable sleep characterized by Lobe Epilepsy cortical arousals. Temporal lobe epi- lepsy is the most common sleep- b Brief nocturnal seizures related epilepsy, not because of a particular sleep-related predilection, b Prominent motor movements but because of the common nature of b Little or no postictal confusion this seizure type. Frontal lobe seizures b Frequent clusters have the greatest penchant to occur b out of sleep. Approximately 61% of Often misdiagnosed as sleep disorder frontal lobe seizures begin during sleep, as opposed to 11% of temporal b Involves the neuronal nicotinic " lobe seizures. Temporal lobe seizures acetylcholine receptor 4 (CHRNA4) subunit are more likely to generalize when they originate from sleep, and nocturnal b Two genetic loci identified temporal lobe epilepsy is thought to (20q13.2-3 and 15q24) portend a more favorable outcome fol- b Mutations in neuronal nicotinic lowing epilepsy surgery.54 acetylcholine receptor genes Autosomal dominant nocturnal fron- CHRNA4 and CHRNB2 tal lobe epilepsy is a distinct clinical

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 8-5 Pearls for Differentiating Non–REM Parasomnias From Nocturnal Frontal Lobe Epilepsy

Non–REM Nocturnal Frontal Lobe Event Characteristic Epilepsy Timing in the sleep period Early Anytime Sleep stage Non-REM N3 Any, but Non-REM N2 is most common Epileptiform discharges seen on No Yes or no Stereotypia present No Yes Awakening No Yes Duration of event 30 seconds to 30 seconds to 30 minutes 2 minutes Postevent confusion Yes Typically minor or state-dependent epilepsies. Sleep is unknown, sleep deprivation likely deprivation activates epileptiform dis- activates epileptiform discharges charges on sleep-wake EEGs and is there- through direct effects of sleep loss. fore useful in evaluation of suspected Neurologists should be aware that sleep epilepsy. Although the exact mechanism deprivationYprovoked seizures may Case 8-2 A 28-year-old man was brought to clinic by his wife with the complaint that he was waking up screaming and thrashing at night. This had begun about 6 months earlier and occurred approximately every 2 weeks. The events would occur at any time of the night, but were slightly less likely during the final portion of the sleep period. The patient would awaken abruptly, thrashing and screaming incoherently. The events lasted about 30 seconds and ended abruptly; the patient may or may not have any memory of the event. The duration and characteristics of the event were consistent over time. Neither the patient nor his family had a history of , head injury, , or epilepsy. His neurologic examination and routine EEG results were normal. He was admitted for 7 days of inpatient EEG monitoring during which two typical events were captured, but no ictal EEG correlate was found. The events resolved with a treatment trial of carbamazepine. Comment. This case of nocturnal frontal lobe epilepsy highlights the difficulty in differentiating nocturnal seizures from parasomnias. In this case, the events are stereotypic, have no predilection for the first third of the night (when non-REM sleep stage N3 is more prominent), are brief, and lack substantial postevent confusion, thereby arguing in favor of a diagnosis of nocturnal frontal lobe epilepsy. The lack of a family history suggests this is not the heritable type. Although events were captured on EEG monitoring, the lack of an ictal correlate does not obviate the diagnosis, as deep mesial frontal generators may insidiously trigger the events. The correct management in this case is a treatment trial, which if successful, helps confirm the diagnosis.

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KEY POINT h Medication side effects alter seizure semiology and therefore effects on sleep quality or duration and should always be not confuse these as nonepileptic events. acute and chronic effects of intermittent considered as a cause of Compared to the general popula- hypoxia and sympathetic activation sleepiness in a patient tion, patients with epilepsy experience on epileptogenic regions of the brain. with epilepsy. substantially more sleep disturbance, The reverse is also true: SDB is more characterized by increased sleep latency prevalent in patients with epilepsy than and number of awakenings during night in the general population.58 Depending as well as alterations in normal sleep on epilepsy severity and SDB definition, architecture due to seizures, interictal between 20% and 80% of epilepsy pa- epileptiform discharges, or medication tients have been reported to have side effects (Table 8-6).56 Nearly two- comorbid SDB.59 In a study of refractory thirds of patients with epilepsy have ex- epilepsy patients, 33% were found to cessive daytime sleepiness as defined by have OSA, with seizures more likely to the Epworth Sleepiness Scale, and night occur at night than during the day. awakening is more common in patients Postulated reasons for this association with epilepsy than in normal controls, include antiepileptic drugYassociated with increased seizure frequency por- weight gain (eg, valproate, ), tending increased sleep disturbance. hypothyroidism, polycystic ovarian dis- Epilepsy is more prevalent in patients ease, and the effect of chronic epilepsy with SDB than in the general popula- on brainstem respiratory control centers tion.57 Possible reasons include OSA and nuclei involved in airway patency.

a TABLE 8-6 Effect of Antiepileptic Drugs on Sleep

Effects on Sleep Effects on Sleep Disorders Stage Stage Stage Drug Efficiency Latency N1 N2 N3 REM Improves/Treats Worsens Phenobarbitol Y , Y j 0 , Sleep-onset Obstructive insomnia sleep apnea (OSA) Phenytoin 0 , jj,0or, None known None known Carbamazepine 0 0 0000Restless legs RLS syndrome (RLS) Valproate Y 0 j,0 0 None known OSA Ethosuximide YYj Y , Y None known None known Gabapentin 0 0 0 0 jjRLS OSA Lamotrigine 0 0b 0 j,jNone known None known Topiramate 0 , 0000OSAc None known Tiagabine YYYYj Y Insomnia None known Levetiracetam YYYYj Y None known None known j YYYj Y None known OSA REM = rapid eye movement; j = increase; , = reduction; Y = not reported; 0 = no change. a Reprinted with permission from Eriksson SH, Curr Opin Neurol.54 journals.lww.com/co-neurology/pages/articleviewer.aspx?year=2011& issue=04000&article=00014&type=abstract. b Lamotrigine may be associated with insomnia. c Due to change in weight.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 63 KEY POINTS and may AD. Degeneration of cholinergic neu- h When approaching a cause suppression in responsiveness of rons in the SCN and ventrolateral pre- sleep problem in a patient and oxygen desaturation optic nucleus, critical for homeostatic with neurodegenerative and increase upper airway musculature maintenance of the circadian rhythm disease, medication side relaxation. Vagus nerve stimulation treat- and sleep initiation, leads to sleep-wake effectsshouldalwaysbe ment for epilepsy has been reported to disturbances in AD. Sundowning, char- considered as a causative increase airway disturbance during sleep acterized by confusion, wandering, factor, particularly with in some patients.60 This therapy is hyperactivity, restlessness, and agitation, cholinergic, , thought to increase airway resistance is common and typically occurs during and from increasing lateral laryngeal muscular low-light hours in the late afternoon and medications. tone or by interfering with the respira- early evening in these patients. People h Sundowning is common tory sensory feedback. with mild to moderate dementia spend in patients with Seizure control may improve with 15% of the day napping, while those neurodegenerative treatment of OSA. In one study, treat- with severe dementia spend 29% of the diseases; treatment is best ment of OSA produced a 50% or greater day napping, which leads to further focused on nonpharmacologic reduction of seizures, with some patients sleep difficulty at night. Cholinergic measures, such as becoming seizure free. Excessive day- medications, the primary treatment for improved time sleepiness also improved, despite AD, can cause insomnia and and a consistent daytime no changes or higher doses of antiepi- disturbances. Sedative-hypnotic medica- schedule, that include 61 leptic drugs. Another study showed tions, used for sleep induction or light exposure and that children with epilepsy treated sur- behavioral modification in AD, can have regular physical activity. gically for their SDB had a 53% median significant side effects such as sleep seizure reduction, with about one-third disruption and increased injury risk. becoming seizure free.62 For all these Antipsychotic medications, if used for reasons, symptoms of daytime sleepi- agitation or sleep induction, can cause ness and poor sleep should not neces- daytime . Melatonin is sarily be considered the result of sometimes used to regulate circadian epilepsy until other causes have been rhythms but may not be effective as evaluated. Epilepsy patients should be monotherapy for sleep disturbances routinely asked about these symptoms in these patients. Nonpharmacologic and referred to a sleep specialist when treatments, including light therapy, ex- appropriate with the goal of improving ercise, and sleep-hygiene modification, quality of life and seizure control. are safe and effective alternatives. In PD, muscle rigidity, tremors, and NEURODEGENERATIVE dystonia can lead to difficulty with sleep DISEASES AND SLEEP initiation and maintenance. Carbidopa- Neurodegenerative diseases, such as Alz- levodopa, used to treat PD, may cause heimer disease (AD) and PD, are com- and insomnia. Depression monly associated with sleep disorders and anxiety (and antidepressants such as such as SDB, RBD, , selective serotonin reuptake inhibitors) insomnia, and circadian rhythm sleep may also perpetuate insomnia in these disorders (Table 8-7). Sleep disruption patients. in people with neurodegenerative disease Cell loss in brainstem nuclei that may lead to worsened cognitive status modulate , along with bulbar and functional ability, increased caregiver and diaphragmatic muscle dysfunction, burden, and perhaps, most importantly, increase the risk of SDB in neurodege- hastened institutionalization. nerative disease. Patients with PD are at Persistent sleep disturbances are risk of developing SDB due to hypoki- present in up to 44% of patients with nesia and rigidity causing upper airway

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TABLE 8-7 Prevalence Estimates of Sleep Disorders in Neurodegenerative Disorders

Sleep-Disordered REM Sleep Restless Legs Disorder Breathing Hypersomnia Behavior Disorder Syndrome Parkinson disease Obstructive sleep apnea 20Y50% 25Y50% Up to 52% (OSA): 27Y52% (sleep attacks (apnea-hypopnea index 1Y20%) [AHI] 95 events/h) 21Y34% (AHI 915 events/h) 4Y15% (AHI 930 events/h) Multiple system OSA: 15Y37% 28Y50% 69Y90% 28% atrophy Stridor: 30Y42% Central sleep apnea (CSA): present Cheyne-Stokes respiration: present Dementia with Not characterized Present 950% No known Lewy bodies association Alzheimer disease OSA: 70Y80% (AHI 95 Up to 69% Case reports support No known events/h) this association association Up to 53% (AHI 910 events/h) 38Y48% (AHI 920 events/h) Spinocerebellar Stridor (SCA types 1 SCA type 3: SCA type 2: 80% SCA type 3: ataxia (SCA) and 3): present 45% 30Y55% OSA (SCA type 3): SCA type 3: 46% SCA types 1 20Y25% and 6: 23% SCA type 2: 18% ALS Sleep-disordered 23% No known 19Y25% breathing: 17Y76% association Hypoventilation (most common) CSA OSA REM = rapid eye movement.

obstruction, restrictive lung disease (ie, moderate AD, treatment of OSA with chest wall rigidity and postural abnor- CPAP improves nocturnal sleep qual- malities), and autonomic dysfunction. ity and excessive daytime sleepiness. However, patients with PD tend to have However, compliance with CPAP is a lower body weight, which reduces OSA challenge in this population. Donepezil occurrence. SDB may also be worsened has been shown to improve OSA in AD, by antianxiolytic and pain medications likely by stimulating the neurochemical prescribed for these patients. In mild to regulation of breathing during sleep.64

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS Central sleep apnea and Cheyne- ting factors specific to SDB in myopa- h REM sleep behavior Stokes breathing pattern can be observed thies include weakness of oropharyngeal disorder can in neurodegenerative diseases and are muscles, tonsillar hypertrophy, obesity, herald preclinical related to degeneration of the ventral and craniofacial dysmorphias. Breathing synucleinopathies, and arcuate nucleus and the pre-Bo¨tzinger alterations become particularly evident as such patients with complex of the medulla (neural areas during REM sleep when respiration REM sleep behavior responsible for respiratory chemosensi- becomes diaphragm dependent. Central disorder should be tivity and rhythmogenesis).65 Stridor in apneas due to alterations in central re- followed for signs and patients with or spiratory drive may be present. Frequent symptoms of these certain spinal cerebellar ataxias and nocturnal awakenings, daytime sleepi- diseases over time. nocturnal hypoventilation in ALS are ness and fatigue, morning headaches, h Indicators of associated with increased mortality.66 and difficulty concentrating should cue sleep-disordered Excessive daytime sleepiness is fre- the practitioner to perform an over- breathing in patients quent in patients with neurodegenerative night polysomnogram and check for with neuromuscular disorders. The degree of excessive day- laboratory evidence of hypoxia and disorders include disrupted nocturnal time sleepiness correlates with the . Diurnal hypercapnia is 67 sleep, daytime sleepiness severity of AD. Sleep attacks can occur indicated by a PaCO2 greater than 45 and fatigue, morning in patients with PD and dementia with mm Hg. Nocturnal hypoventilation is headache, and trouble 68 Lewy bodies. Dopamine agonists, used defined as a PaCO2 greater than 55 mm concentrating. to treat symptoms such as tremor in PD, Hg for 10 minutes or more or a 10 mm 69 may also induce sudden sleep attacks. Hg or greater increase in PaCO2 during RBD (Supplemental Digital Content sleep (in comparison to an awake su- 8-1, links.lww.com/CONT/A19) is asso- pine value) to a value exceeding 50 mm ciated with disruption of the normal Hg for 10 minutes or more. Nocturnal paralysis-inducing mechanisms of REM hypoxia can be indicated by a low mean sleep and may herald the onset of PD saturation, high desaturation index, and or other synucleinopathies by 20 years or more (Figure 8-2).70 Dream-enacting behaviors can lead to injury to the pa- tient or partner and are typically treated with clonazepam or melatonin (Case 8-3). In PD, an increased fre- quency of restless legs syndrome and periodic limb movement disorder may be present, especially in patients not treated with levodopa.71

NEUROMUSCULAR DISEASE AND SLEEP In general, sleep disorders from neuro- muscular diseases occur because of sleep-related ventilatory difficulties (and respiratory failure), particularly in later FIGURE 8-2 Survival curve of patients with idiopathic REM sleep behavior disorder. At 5 years’ survival stages of the disease. Respiratory com- time, 17% of patients went on to develop a promise may be related to diaphragmatic neurodegenerative disorder, and at 10 years’ survival time, weakness, restrictive lung disease from 40% of patients developed a neurodegenerative disorder. intercostal muscle weakness, kyphosco- Modified from Postuma RB, et al, Neurology.68 B 2009, with permission from American Academy of Neurology. www.neurology.org/content/72/ liosis, or pulmonary microatelectasis 15/1296.abstract. from chronic hypoventilation. Contribu-

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Case 8-3 A 68-year-old, right-handed man presented with symptoms of loud snoring and nocturnal awakenings related to nocturia and in which he is fighting off an animal such as a lion or an ape. He would awaken from these dreams swinging his arms and yelling and in the past had struck his wife in bed. He found these behaviors embarrassing since they had occurred on long plane flights and tour bus rides. His medical history included lumbar stenosis, prostate carcinoma status-post resection, and diverticulosis. He took a baby aspirin, multivitamin, and calcium daily. He had no family history of neurodegenerative disease, but two brothers also had undiagnosed dream-enacting behaviors. His vital signs were within normal range, he was not orthostatic, body mass index was 24 kg/m2,and general examination was nonrevealing. His MiniYMental State Examination score was 29/30. No signs of dysarthria, hypophonia, or ataxic speech were present, and the remainder of the neurologic

FIGURE 8-3 Thirty-second polysomnogram fragment showing increased chin tone in REM sleep and limb movements. Channels are as follows: electrooculogram (left: LOC-A2, right: ROC-A1); chin EMG (Chin1-Chin2); EEG (left central [C3-A2], right central [C4-A1], left occipital [O1-A2], right occipital [O2-A1]), two ECG channels; limb EMG (LAT1-LAT2); snore channel; nasal-oral airflow (N/O); respiratory effort (thoracic [THOR], abdominal [ABD]); and oxygen saturation (SpO2). Tonic EMG activity is consistent with REM sleep behavior disorder when present in more than 50% of the total 30-second epoch duration with an amplitude of at least twice the background EMG muscle tone or more than 10 6V. Phasic EMG activity includes any burst of activity lasting between 0.1 and 5.0 seconds with an amplitude exceeding twice the background EMG activity irrespective of its morphology. The green arrow points to increased muscle tone in the chin EMG lead while the blue arrow points to increased muscle tone in the limb EMG lead.

Figure courtesy of Alon Y. Avidan, MD, MPH, FAASM.

Continued on page 163

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examination results were normal. Overnight polysomnography showed minimal sleep-disordered breathing, oxygen desaturation nadir of 91%, and increased muscle tone during REM sleep (Figure 8-3). No epileptiform discharges were seen. Clonazepam 0.5 mg nightly was prescribed, and the patient was ensured a safe sleeping environment. He tolerated the medication, and the dream-enacting behaviors ceased. During the next 2 years, no signs of tremor, gait impairment, or dementia were apparent. Comment. This case of REM sleep behavior disorder (RBD) highlights protean aspects of the disease. This disorder typically involves older men, can precede the onset of synucleinopathies such as dementia with Lewy bodies in some but not all patients, and may result in substantial injury to patients or their bed partners. Increased chin EMG tone in REM sleep is the polysomnographic hallmark of the disease. Exposure to selective serotonin reuptake inhibitors or tricyclic antidepressants can provoke the disorder. Treatment focuses on creating a safe sleeping environment (eg, remove sharp furniture edges and mirrors, lock doors, close windows) and benzodiazepines, most commonly clonazepam. Melatonin and dopamine agonists have also been used with some success. All patients with RBD should undergo a thorough neurologic examination and be followed over time for evidence of . In the event of focal findings, neuroimaging is recommended since RBD can also be precipitated by brainstem lesions of almost any cause. high hypoxemic burden such as an is average volume-assured pressure sup- KEY POINT oxygen saturation of 88% or less for 5 port, which automatically adjusts pres- h Objective tests indicating consecutive minutes. Other indicators sure support to maintain a target tidal nocturnal hypoventilation of SDB in neuromuscular disease in- volume. Regardless of NPPV type or set- in neuromuscular disease include daytime PaCO clude a maximal inspiratory pressure of tings, supplemental oxygen may also be 2 greaterthan45mmHg, less than 60-cm water and a forced vital required and tracheostomy becomes a 72 nocturnal oximetry capacity of less than 50% predicted. consideration in advanced disease. showing oxygen Daytime predictors of sleep hypoventi- type 1 (DM1) is saturation of 88% or less lation in Duchenne muscular dystro- the most common adult-onset form of for 5 consecutive phy are a forced expiratory volume of muscular dystrophy, and hypersomnia minutes, nocturnal less than 40% and a base excess greater is a key clinical feature of the disease. PaCO2 of greater than than 4 mmol per liter.73 Subjective and objective sleepiness (as- 55 mm Hg for 10 Noninvasive positive-pressure ventila- sessed by the Epworth Sleepiness Scale minutes or more or a 10 tion (NPPV) is the most common initial and multiple sleep latency test, respec- mm Hg or greater treatment for SDB in neuromuscular tively) is present in 70% of patients with increase in PaCO2 during disorders and improves survival and DM1.75 Excessive daytime sleepiness in sleep (compared to wake) to a value quality of life in patients with ALS.74 This DM1 is frequently persistent and unaf- exceeding50mmHgfor may involve bilevel positive airway pres- fected by napping, unlike that of patients 10 minutes or more, sure with expiratory pressure set to pre- with narcolepsy, who tend to feel maximal inspiratory vent airway obstruction and inspiratory refreshed after . Patients with DM1 pressure of less than pressure set for ventilation purposes. frequently meet diagnostic criteria for 60-cm water, and forced Ventilation is often a greater concern narcolepsy, and methylphenidate and vital capacity of less than than airway obstruction and may nec- modafinil are effective treatments for 50% predicted. essitate pressure-support windows as sleepiness in these patients. Regarding large as 10-cm water or more. In many myasthenia gravis, 40% to 60% of cases, the presence of central apneas clinically stable patients have SDB.76 necessitates a back-up rate to deliver a Insomnia is associated with neuro- breath if the patient fails to trigger an muscular diseases and often induced by inspiratory effort. Another NPPV option steroids for treatment of disorders such

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KEY POINTS h When treating patients as inflammatory myopathies. PLMS are increased risk of fatigue in MS. Sleepi- with neuromuscular increased in DM1 compared to controls ness and fatigue in MS are commonly 77 disorders with bilevel and associated with sleep disturbance. treated with modafinil, although its ef- positive airway pressure, Lastly, restless legs syndrome is increased fectiveness is uncertain. improving ventilation is in ALS and associated with increased Narcolepsy and RBD occur more often more important sleep complaints.78 frequently in patients with MS. Case than relieving airway reports suggest an association between obstruction, and wide acute disseminated pressure-support windows AND SLEEP and neuromyelitis optica with hyper- may be necessary. As with stroke or tumor, lesion location somnia and secondary narcolepsy. h Multiple sclerosis lesions in multiple sclerosis (MS) is critical to Insomnia is common in MS, present in in brain areas the presence or absence of sleepiness, up to 40% of patients. Common MS subserving sleep onset, insomnia, or specific sleep disorders. symptoms, such as pain, spasticity, blad- alertness, and REM Hypothalamic lesions involving the tuber- der dysfunction, depression, anxiety, can omammillary nucleus or hypocretin/ and medications (ie, immunomodula- precipitate insomnia, orexin production can cause sleepiness. tors, such as interferon and corticoste- sleepiness, and REM sleep behavior disorder. Pontine lesions involving areas such as roids) all likely contribute to difficulty the sublaterodorsal tegmental nucleus falling and staying asleep. Restless legs h Insomnia is common in can precipitate RBD. Lesions involving syndrome may be seen in MS patients multiple sclerosis and the ventrolateral preoptic nucleus can and is associated with greater disabil- likely due to many 86 disease-related factors, predispose to insomnia. For these rea- ity, although these symptoms may be such as pain, spasticity, sons, attention to lesion location on confused with other frequent MS com- bladder dysfunction, neuroimaging can prove insightful when plaints such as paresthesias, dysesthe- depression, anxiety, and addressing sleep concerns in MS. sias, pain, and spasticity. PLMS are also 84 medication side effects. Fatigue and sleepiness are common highly prevalent in MS. Intrathecal h Sellar or suprasellar complaints in MS and are frequently baclofen, for treatment of spasticity, malignancies can intertwined. In a cross-sectional survey reducesPLMSbutincreasesobstructive indirectly cause of 1063 people with MS, those with MS and central respiratory events, especially sleep-disordered had more sleep disturbances (and day- in patients receiving bolus compared to breathing by time ) compared to a group continuous intrathecal administration.87 endocrinologic of chronically ill patients and a group of Generally speaking, poor sleep in MS is dysfunction causing healthy individuals.79 Conversely, multi- an independent predictor of quality of obesity. ple studies dispute sleepiness as an MS life.88 symptom.80,81 Fatigue may be related to sleepiness, as sleep disruption can CNS MALIGNANCIES AND SLEEP cause or worsen fatigue through CNS Malignancies disrupt sleep through both activation and increased inflammation. direct and indirect effects. Cerebral tu- When focusing on fatigued subsets of mors, especially those located in the MS patients, those with fatigue are sig- sellar or suprasellar regions (ie, cranio- nificantly sleepier than nonfatigued pharyngioma, pilocytic astrocytoma, and patients with MS,82,83 although this is pituitary adenoma) can induce sleepi- disputed by other studies showing ness through direct neoplastic involve- normal Epworth Sleepiness Scale scores ment or pressure exertion on the and sleep latencies on the multiple hypothalamus, with a corresponding sleep latency test between the two reductioninhypocretin(orexin)asthe groups.84,85 SDB is more frequent in likely causative factor. Sellar or supra- fatigued (27.0%) versus nonfatigued MS sellar tumors may also cause endo- patients (2.5%), and the presence of a crine dysfunction, indirectly producing sleep disorder is associated with an sleepiness and sleep disturbances by

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT promoting obesity and subsequent OSA. a risk factor for stroke and, as with all h Secondary narcolepsy Insomnia in these patients may result stroke risk factors, its investigation can occur from from alterations in melatonin production should be considered in every TIA and treatment of CNS by the pineal gland. Brainstem gliomas stroke patient for secondary prevention. malignancies with and hemispheric tumors (ie, those Whether diagnosing and treating SDB is surgical resection or with bilateral hemisphere invasion or a good stroke primary prevention strat- radiation therapy in the edema causing increased intracranial egy is yet to be definitively determined, perihypothalamic region. pressure and/or cerebral herniation) but in the meantime it is probably have also demonstrated somnogenic reasonable and safe to assume that capabilities, with disruption of the re- treating SDB will positively affect future ticular activating system as the likely risk of cerebrovascular disease. Sleep cause. In addition, paraneoplastic dis- affects all headache disorders, and two orders such as anti-Ma2 encephalitis disorders (hypnic and sleep apnea head- are associated with sleepiness.89 Nu- ache) are sleep specific and may occur merous case reports document secon- upon awakening. Neurodegenerative dary narcolepsy and sleepiness related diseases, MS, and CNS malignancies to treatment of cerebral tumors with can influence sleep quality, continuity, radiation and surgical instrumentation and sleepiness and precipitate SDB or and/or resection. Radiation therapy has RBD by involving nuclei and pathways been implicated in ‘‘somnolence syn- involved in automatic control of respira- drome,’’ a poorly described hypersomnia tion, dream-related paralysis, alertness, in children receiving cranial irradiation and circadian rhythmicity. for acute lymphocytic leukemia. Chemo- therapeutics and immunomodulators VIDEO LEGEND used to treat cerebral tumors may Supplemental Digital Content 8-1 induce insomnia or somnolence. Meth- REM sleep behavior disorder. Video montage of REM sleep behavior disorder demonstrating ylphenidate, amphetamines, and modafi- vigorous, aggressive, and violent behaviors during nil are effective in the treatment of REM sleep in an older adult male patient. Note sleepiness in children with brain tumors. violent and aggressive dream enactment correlat- SDB may be caused by tumors in- ing with dream sequence, placing both the pa- volving the brainstem leading to dys- tient and the bed partner at risk for injury. function of the respiratory centers and links.lww.com/CONT/A19 B nuclei involved in diaphragmatic and 2013 Carlos Schenk, MD. Used with permission. bulbar muscle control. RBD may pre- sent when a brainstem lesion disrupts REFERENCES 1. Shahar E, Whitney CW, Redline S, et al. the normal paralysis-inducing mecha- Sleep-disordered breathing and nisms of REM sleep. Restless legs syn- cardiovascular disease: cross-sectional results drome has been described as the initial of the sleep heart health study. Am J Respir Y complaint in a patient with a foramen Crit Care Med 2001;163(1):19 25. magnum tumor,90 andPLMShavebeen 2. Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the observed in patients with thoracic spi- occurrence of stroke. Am J Respir Crit Care 91 nal cord tumors. Med 2005;172(11):1447Y1451. 3. Munoz R, Duran-Cantolla J, Martinez-Vila E, CONCLUSIONS et al. Severe sleep apnea and risk of ischemic Sleep dysfunction and neurologic disor- stroke in the elderly. Stroke 2006;37(9): Y ders are deeply intertwined, and the 2317 2321. neurologist is well served to consider 4. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident the interaction of sleep with almost stroke: the sleep heart health study. Am J every patient entering the clinic. SDB is Respir Crit Care Med 2010;182(2):269Y277.

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