Review Article Address correspondence to Dr Nathaniel F. Watson, Harborview Medical Center, Sleep 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 Sleep Medicine 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 breathing (SDB) is a risk factor for cerebrovascular Use Disclosure: Drs Watson and Viola-Saltzman report no disease and should be considered in all TIA and stroke patients. Sleep disorders can disclosures. amplify nociception and worsen headache disorders; and some headaches, including * 2013, American Academy those related to SDB and hypnic headache, are sleep specific. REM sleep behavior of Neurology. disorder may be an early sign of neurodegenerative disease. Focal lesions of almost any etiology (eg, multiple sclerosis and CNS malignancies) in the hypothalamus, basal forebrain, or brainstem may result in sleep disturbance, sleepiness, and insomnia. Sleep-related hypoventilation and fatigue are common in neuromuscular disease. SDB and epilepsy 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. Continuum (Minneap Minn) 2013;19(1):148–169. 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 nervous system. 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 CEREBROVASCULAR DISEASE 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 heart rate. 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 148 www.aan.com/continuum February 2013 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 (Strokes) 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 sleep apnea (apnea-hypopnea 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 obstructive sleep apnea (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 myocardial infarction, 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 Continuum (Minneap Minn) 2013;19(1):148–169 www.aan.com/continuum 149 Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Comorbid Neurologic Disorders 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 atrial fibrillation 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 hypoxia pnea.15 Resistant hypertension is defined in OSA increase oxidative stress and as blood pressure that requires four or vascular inflammation, 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