Sleep and

Kimberly Nicole Mims, MDa, Douglas Kirsch, MDb,*

KEYWORDS Stroke Obstructive sleep RLS/PLMS Cerebrovascular accident       Central Sleep duration   

KEY POINTS Growing evidence suggests that sleep amount and sleep disorders may impact risk for stroke;  conversely, the cerebrovascular events may change sleep drive and affect breathing patterns dur- ing sleep. Treatment of sleep disorders, whether causative of stroke or caused by stroke, will likely improve  sleep-related symptoms and may improve further stroke risk and long-term outcomes. Sleep apnea, both obstructive and central, is strongly associated with increased cerebrovascular  events. Other sleep disorders, including insomnia, RLS/PLMS, and parasomnias may also result in  increased incidence of stroke. Short and long sleep duration increase cardiovascular events by increasing sympathetic tone and  low-grade inflammation. Treatment of sleep disorders reduces sleep disruption and can improve functional stroke outcome  as well as decrease stroke risk.

Strokes are one of the most common causes of Central sleep apnea (CSA) occurs when respira- death in the United States.1 Growing evidence tory effort is decreased or absent and is commonly suggests that sleep amount and sleep disorders associated with conditions such as heart failure. may impact risk for stroke; conversely, the cere- The most widely accepted epidemiologic data brovascular events may change sleep drive and project that 4% of men and 2% of women suffer affect breathing patterns during sleep. This article from OSA,2 although more recent data suggest describes the most up-to-date information on the that the incidence of sleep apnea in highly devel- linkage between sleep and stroke and attempts oped countries could be as high as 20% in men to demonstrate how some physicians may use and 10% in women.3 changes in sleep to limit the risk of stroke in In patients with a history of stroke or transient some patients. ischemic attack, sleep apnea incidence is signifi- cantly higher than the general population, with SLEEP APNEA AND STROKE estimates suggesting 72% for apnea-hypopnea index (AHI) >5/h and 38% for AHI >20/h.4 In a small Sleep apnea is defined by decreased airflow study evaluating sleep-disordered breathing (SDB) occurring during sleep. Two main types of sleep incidence in an inpatient stroke rehabilitation unit, apnea exist: obstructive and central. Obstructive 91% demonstrated AHI >10/h with a mean AHI of sleep apnea (OSA) is the most common type of 32/h.5 Furthermore, several prospective cohort sleep apnea and consists of complete or partial studies indicate increased risk of cardiovascular occlusion of the airway, usually accompanied by events in patients with OSA; OSA serves as an in- an associated oxygen desaturation or arousal. dependent risk factor for cardiovascular events.6–9

a Charlotte Medical Clinic, Carolinas HealthCare System, 1001 Blythe Boulevard, Suite 403, Charlotte, NC 28203, USA; b CHS , Carolinas HealthCare System, 1601 Abbey Place, Building 2, Suite 200, Char- lotte, NC 28209, USA * Corresponding author. E-mail address: [email protected]

Sleep Med Clin - (2015) -–- http://dx.doi.org/10.1016/j.jsmc.2015.10.009

1556-407X/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved. sleep.theclinics.com 2 Mims & Kirsch

The American Heart Association recommends been implicated in worsening dyslipidemia, oxida- screening for OSA for stroke prevention and sug- tive , and endothelial dysfunction and inflam- gests treatment is reasonable, although its effec- mation. In addition, OSA is associated with a tiveness for primary prevention of stroke remains significant increase in carotid intima-media thick- unknown.10 ness and arterial stiffness evidenced as an early The 2014 recommendations by the American indication of atherosclerosis. Heart Association include stratification of antith- Intermittent hypoxia contributes to dyslipidemia rombotic therapy based on CHA2DS2-VASc score, by increasing levels of very low-density lipoprotein which does not incorporate the presence of sleep (VLDL) secretion. This increased secretion is medi- apnea. A retrospective cohort study by Yaranov ated by upregulation of stearoyl coenzyme A desa- and colleagues11 revealed that patients who had turase 1, which increases in direct proportion to atrial fibrillation and OSA developed stroke more severity of nocturnal hypoxia.17 Decreased lipo- commonly than atrial fibrillation patients without protein clearance also contributes to an increase OSA (odds ratio 3.84). in circulating VLDL. Lipoprotein lipase contributes to clearing circulating lipoproteins, and intermit- tent hypoxia inhibits its activation. Patients with Pathology of and OSA who used positive pressure therapy as treat- Stroke ment had increased lipoprotein lipase activity.18 Although the specific causal mechanism linking sleep However, several other studies contradict a rela- apnea to increased strokerisk hasyet tobeidentified, tionship between OSA and dyslipidemia, and addi- several direct and indirect relationships contributing tional studies have been suggested to further to atherosclerosis are known. Atherosclerosis, tradi- investigate the relationship.19 tionally viewed as solely a disease of lipid storage, is Intermittent hypoxia resulting from OSA is highly now thought to be multifactorial, with several pro- associated with oxidative stress. Oxygen free rad- cesses contributing to plaque development. Factors icals lead to lipid peroxidation, which are acquired contributing to atherosclerotic development include more easily by macrophages; this causes macro- hypertension, metabolic syndrome (, dysli- phage foaming and provides a substrate for the pidemia), and smoking. Inflammatory mediators of progression of the atherosclerotic plaque.17 atherosclerosis include markers of systemic inflam- Although most studies verify an increase in lipid mation (eg, interleukin [IL]-6, C-reactive protein peroxidation and oxidized low-density lipoprotein [CRP], intracellular adhesion molecules [ICAMs]), in patients with OSA, the lack of benefit seen fibrinogen, and lipoprotein (a). with antioxidant therapy raises the question of OSA causes repetitive episodes of decreased whether oxidative stress is a result of vascular oxygenation mimicking asphyxia and results in inflammation instead of atherosclerosis20 (Fig. 1). negative intrathoracic pressure. Increased arousals OSA is also correlated with an increase in in- from sleep occur in response to decreased oxygen flammatory mediators and thought to levels and increased circulating carbon dioxide contribute to endothelial dysfunction. A direct pro- levels. Arousals during sleep increase sympathetic portional relationship is observed with elevation of activation, resulting in brief increases in blood pres- inflammatory markers in patients with increased sure. Patients with OSA demonstrate increased AHI, resulting in increased serum levels of markers, incidence of refractory hypertension, perhaps as a including CRP and IL-6. Several studies indicated result of the changed nocturnal blood pressure.12 an increase in CRP was independently associated OSA may also cause insulin resistance resulting in with OSA and nocturnal hypoxemia, although con- diabetes mellitus type 2,13 thought to be secondary tradictory studies found increased CRP to be more to an increase in circulating cortisol. Leptin, a hor- independently associated with body mass index mone released by adipocytes in response to food, (BMI) than OSA severity. IL-6, responsible for CRP is decreased in patients with OSA, lowering their production by the liver, also increases in patients metabolic rate, decreasing the sensation of full- diagnosed with OSA compared with those without, ness, and contributing to metabolic syndrome and although contradictory studies exist linking this increased weight gain.14 mediator to BMI as well.21 Intracellular adhesion The predominant abnormality of OSA stems from molecules, which facilitate leukocyte adhesion to intermittent hypoxia occurring during apnea and vascular endothelium, increase in OSA patients hypopnea events. In several mice models, intermit- compared with controls, and they increase in direct tent hypoxia resulted in increased formation of fatty proportion to nocturnal hypoxemia.22 OSA and streaks in the aortic arch and acceleration in devel- nocturnal hypoxemia severity also increase tumor opment of disease in those genetically prone to necrosis factor-a with additional influence by age atherosclerosis.15,16 Intermittent hypoxia has and BMI.23 Although data are limited on IL-8, Sleep and Stroke 3

Oxidave stress

Endothelial dysfuncon and inflammaon

Inhibion of Insulin lipoprotein Dyslipidemia Diabetes Atherosclerosis resistance lipase

Hypertension

Increased sympathec acvaon

Fig. 1. Intermittent hypoxia during apneic events increases atherosclerosis via multiple mechanisms. selectins, and vascular cell adhesion molecules, that is, large-vessel versus Small-vessel . data suggest these markers are significantly However, no studies have yet demonstrated a sig- elevated in patients with OSA, again associated nificant difference in type of ischemic stroke seen with influence by age and BMI21 (Fig. 2). In har- in patients diagnosed with sleep-disordered vested endothelial cells in patients with OSA, the breathing (SDB) compared with those without. nuclear factor, NF-kB, increased, and nitric oxide Although no significant relationship was seen synthase expression and activity decreased. These between SDB and size of vessel occluded, a sig- changes reversed after treatment of OSA with nificant increase in cardioembolic strokes was continuous positive airway pressure (CPAP) observed in patients with SDB compared with therapy.24 those without.25 Notably, most studies assessing this question rely on a diagnosis of SDB after stroke occurred. Stroke Subtypes Respiratory changes are commonly seen acutely Several investigators questioned whether OSA after stroke and can be correlated to stroke loca- predisposes to certain ischemic stroke types, tion. Respiratory apraxia results from strokes in

Fig. 2. OSA increases the risk of atherosclerosis and plaque forma- tion by increasing inflammatory me- diators, including (A) CRP, (B) IL-6, (C) ICAMs, and (D) tumor necrosis factor-a. 4 Mims & Kirsch

the frontal lobe, basal ganglia, or internal capsule. and intelligence. These patients also had a signifi- Neurogenic hyperventilation occurs after pontine cantly increased length of stay in the rehabilitation strokes; apneustic respirations can result after unit and were less functionally independent on strokes in the inferior medial posterior area of the discharge from the unit. There was no significant pons; central alveolar hypoventilation syndrome difference in levels of sleepiness, , depres- (Ondine curse) can occur after medullary stroke, sion, or anxiety between the patients with an and medullary strokes at the level of C1 can impair elevated ODI and non-SDB patients. voluntary respiration if stroke localizes posteriorly or automatic respiration if localized anteriorly. Further sleep apnea and stroke studies These respiratory patterns often lack significant One of the most compelling and as of yet unan- prognostic implications, although low carbon diox- swered questions in terms of sleep apnea and ide can be associated with poorer prognosis. The stroke is whether treatment of sleep apnea im- mean prevalence of respiratory changes presenting proves neurologic outcome. Although there are in the acute poststroke period is 59%, with OSA be- several prospective cohort studies available ing the most common respiratory disorder.26 demonstrating improved functional outcome with CPAP treatment of sleep apnea, the control popu- Central sleep apnea lation typically consists of nonadherent patients, CSA is defined by a cessation or decrease of venti- thus introducing selection bias. No studies have latory effort during sleep and is usually associated been performed with sham CPAP treatments in with an oxygen desaturation. CSA is seen in up to this setting, arguably because of ethical consider- 26% of patients following a stroke, but the CSA ation of nontreatment in diagnosed sleep apnea often improves as acuity of stroke decreases.27 patients. A few studies are underway, most CSA is often a result of anterior circulation le- notably TOROS, to provide a reliable answer to sions.28 In addition, the incidence of CSA increases whether treating sleep apnea significantly im- in patients with larger strokes and strokes associ- proves functional outcome after stroke. ated with significant mass effect.29 The presence Further studies are also necessary to assess the of CSA after stroke portends poorer prognosis causal relationship between several correlative factors seen in stroke and sleep, including dyslipi- despite higher minimum SaO2 levels observed in patients with central respiratory events compared demia, hypertension, and atrial fibrillation. with those without central respiratory events.28 Treatment of CSA after stroke includes CPAP ther- INSOMNIA AND STROKE apy and adaptive servoventilation (ASV), although use of ASV is currently controversial in patients Insomnia is defined as persistent difficulty with with predominant CSA, and moderate to severe sleep initiation, duration, consolidation, or quality congestive heart failure has recently been based that occurs despite adequate opportunity and cir- on the mortality data from the SERV-HF study.30 cumstances for sleep and results in some form of daytime impairment.33 It is the most common Functional outcome after stroke , affecting up to 22% of adults.34 Several studies prove SDB increases incidence Insomnia varies in chronicity, but even in those and recurrence of stroke as well as lowers with remission, 27% experiencing insomnia mortality.31 However, a dearth of studies exists relapse within 3 years.35 detailing functional outcome after stroke in pa- Insomnia is associated with all-cause mortality tients with sleep apnea. Recently, Aaronson and and cardiovascular death, including stroke.36 colleagues32 investigated functional outcome of Insomnia incidence in patients who have had a patients admitted to a neurorehabilitation unit. stroke approaches 57%, with 38% reporting Within 4 weeks of admission, patients received insomnia as a preceding symptom to the stroke.37 several neuropsychiatric tests assessing vigilance, In patients who have had a stroke, insomnia inci- attention, memory, working memory, executive dence is higher in women than in men.38 Living functioning, language, visuoperception, psycho- alone and an older age also increase the risk of motor ability, and intelligence. Within the first few insomnia associated with stroke.39 weeks, an ambulatory overnight cardiorespiratory Short sleep duration is also associated with polygraphy was performed to generate an oxygen increased atherosclerosis risk.40 Postmenopausal desatuation index (ODI, a surrogate index for sleep women reporting short sleep demonstrated a apnea severity). The investigators discovered pa- distinct increased risk for stroke without an in- tients with an elevated ODI demonstrate statisti- crease in clinically apparent cardiovascular dis- cally worse impairment in attention, executive ease.41 A Japanese study demonstrated patients functioning, visuoperception, psychomotor ability, with short sleep time and higher nocturnal systolic Sleep and Stroke 5 blood pressures had a significant increase in car- with multifactorial cause, including complications diovascular events.42 In a similar study on hyper- of hospitalization, stroke, and/or .26 tensive patients, the presence of both diabetes Poststroke insomnia also can also affect stroke re- and short sleep duration also correlated with covery and quality of life. Insomnia increases the risk increased cardiovascular disease than either inde- of subsequent stroke48 and worsens psychological pendently43 (Figs. 3 and 4). health with an associated increase in frequency of Several studies indicate insomnia plays an suicide.49 Poststroke insomnia increases physical important role in the development of cardiovascular disability, symptoms, and anxiety.37 One disease, including stroke, and insomnia can affect study demonstrated patients with fewer days of poststroke outcome and quality of life, if left un- insomnia positively correlated with improvement in treated. Insomnia increases the incidence rate of overall health, energy, family roles, mobility, mood, stroke as identified by a retrospective cohort study personality, social roles, thinking, and work/produc- performed by Wu and colleagues.44 Across all ages tivity asreported by patients on a quality-of-life ques- and both genders, patients with insomnia exhibited tionnaire.38 The same study also demonstrated the a higher incidence rate ratio of stroke compared converse: namely, that an increase in sleepless with those without insomnia. The largest incidence nights resulted in decreasing energy levels, concen- rate ratio was identified in 18 to 34 year olds; the ra- tration, and memory, similar to that reported in the tios then decreased with advancing age, although general population.50 incidence of ischemic stroke increased with advancing age.45 Overall, individuals with insomnia Pathology demonstrated a 54% increased likelihood of devel- oping stroke compared with patients without Proposed mechanisms linking insomnia to stroke insomnia. Wu and colleagues44 also studied focus on the disruption of sleep seen in patients insomnia chronicity and discovered individuals with insomnia. Increased arousals are implicated with persistent insomnia had the highest risk of in increasing sympathetic activity at night stroke, followed by individuals with relapsing compared with the typical lull in sympathetic activ- insomnia. Subjects with insomnia in remission had ity seen during sleep, which results in nocturnal the lowest increased rate of stroke compared with hypertension. In combination with increased acti- other subjects with insomnia but still demonstrated vation of the hypothalamic-pituitary-adrenal axis, a hazards ratio exceeding that of those without cortisol levels elevate, increasing the risk for insomnia. vascular disease.51 Insomnia occurrence after stroke is also In short sleep, nonrestorative sleep correlates increased. Patients with right hemispheric strokes with elevated levels of inflammatory cytokines, reported more insomnia symptoms than those generating a low-grade inflammation state.52 with left hemispheric strokes in one study.46 One Gangwisch and colleagues53 also demonstrated brain area with insomnia as a prominent symptom an association between elevation in sympathetic includes the and , specifically tone and short sleep. the thalamomesencephalic region, pontomesen- Poststroke insomnia may localize to specific le- cephalic region, and/or the pontine tegmentum, sions based on certain symptoms. Supratentorial which can result in inversion of the sleep-wake cy- strokes decrease non-rapid eye movement cle and nighttime agitation.47 Insomnia commonly (NREM) sleep, decrease total sleep time, and develops acutely after stroke, although usually reduce sleep efficiency.54 There is limited

Fig. 3. U-shaped mortality curve for 636,095 women based on self- reported sleep duration. Hazard ratios represent all-cause mortality adjusted for covariates. (From Kripke DF, Garfinkel L, Wingard DL, et al. Mortal- ity associated with sleep duration and insomnia. Arch Gen 2002; 59(2):131–6; with permission.) 6 Mims & Kirsch

Fig. 4. U-shaped mortality curve for 480,841 men based on self-reported sleep duration. Hazard ratios repre- sent all-cause mortality adjusted for covariates. (From Kripke DF, Garfinkel L, Wingard DL, et al. Mortality associ- ated with sleep duration and insomnia. Arch Gen Psychiatry 2002;59(2):131–6; with permission.)

evidence that right hemispheric strokes reduce limiting exposure to “smart” devices (smartphone, rapid eye movement (REM) and REM density, tablet) and backlit screens in the , avoid- whereas left hemispheric strokes decrease ing work or thinking about work in the bedroom, NREM stages.55 Strokes localized to the pontome- and maintaining a dark, quiet environment in the sencephalic junction and the raphe nucleus may bedroom. preferentially reduce NREM sleep without Psychological and behavioral modifications are affecting REM sleep.56 Paramedian thalamas indicated as first-line therapy for insomnia in all strokes and strokes in the lower pons are associ- adults, either independently or coupled with other ated with loss of slow wave sleep but preservation therapies including medications.60 Cognitive of REM sleep.26 Conversely, several studies sug- behavioral therapy, including stimulus control gest strokes in the lower pons may also reduce therapy, sleep restriction therapy, and/or relaxa- REM sleep.57,58 Finally, some studies suggest in- tion therapy, are recommended as standard of fratentorial strokes eliminate sleep spindles, K care for insomnia treatment. complexes, and/or vertex waves, thus changing Pharmacotherapy may supplement cognitive the patterns of NREM behavioral therapy but is recommended to be sleep.58 Finally, changes in sleep architecture restricted to short-term use. The consensus state- associated with decreased functional recovery in ment of use of pharmacotherapy recommends stroke include decreased sleep efficiency, choosing pharmacologic agents based on symp- increased awakenings, decreased stage 2 sleep, tom pattern, treatment goals, past treatment re- decreased sleep spindles and K complexes, and sponses, patient preference, cost, availability of increased stage 3 sleep.59 other treatments, comorbid conditions, contraindi- cations, concurrent interactions, and 60 Diagnosis and Treatment of Insomnia side effects. In stroke patients, sedative hyp- notics should generally be avoided if possible Diagnosis of insomnia is primarily clinical and often because of the risk of increased memory impair- includes a detailed history, a 2-week sleep diary, ment, disorientation, and falls. identification of potential confounding medical and Other treatments specifically evaluated in stroke psychiatric illnesses, and occasionally, quality-of- patients include acupuncture and problem-solving life and daytime functioning questionnaires. Poly- therapy. A double-blinded randomized control trial somnography is only indicated for patients with demonstrated utility of intradermal acupuncture insomnia in instances of insomnia refractory to in reducing insomnia in poststroke patients.61 pharmacologic or cognitive treatment or if another Problem-solving therapy with or without cognitive sleep disorder is suspected. may be behavioral therapy also demonstrated efficacy in used to delineate sleep patterns, especially if the improving insomnia symptoms in stroke patients.62 patient’s sleep perception is difficult to discern.60 However, cognitive behavioral therapy remains the The simplest and perhaps most important treat- recognized standard of treatment for insomnia. ment of insomnia after stroke involves encour- aging appropriate , including AND STROKE limiting exposure to nighttime stimulation and increasing exposure to daylight. Other important Hypersomnia is defined as an “inability to stay practices of appropriate sleep hygiene include awake and alert during the major waking episodes Sleep and Stroke 7 of the day, resulting in periods of irrepressible hypersomnia and mortality discovered that need for sleep or unintended lapses into drowsi- attenuated the relationship between ness or sleep.”33 The prevalence of hypersomnia hypersomnia and increased mortality.73 in the adult population is estimated at 20%.63 In Hypersomnia may present as a result of stroke the stroke population, hypersomnia affects up to as well. Lesions affecting the reticular activating 27% of patients.64 Studies investigating the asso- system (RAS) often result in hypersomnia. These ciation between short sleep duration and stroke lesions include bilateral thalamic lesions, abound, but studies addressing the relationship thalamo-mesencephalic lesions, upper and medial between long sleep duration and stroke are less pontomedullary regions where RAS fibers are prevalent. However, recent investigations reveal highly concentrated.26 Lesions in the cerebral a U-shaped curve demonstrating increased mor- hemispheres tend to be less associated with hy- tality in both short and long sleepers, and a recent persomnia because the RAS fibers are more American Academy of Sleep Medicine consensus diffuse, but large cerebral lesions, lesions affecting statement recommends at least 7 hours of sleep the left more than the right hemisphere, and le- per night for adults, with a qualifier identifying sions affecting the anterior more than the posterior unclear risk of increased mortality with sleep regions result in increased hypersomnia.74 Para- exceeding 9 hours.65 median thalamic infarcts result in the most severe Several studies indicate that sleep exceeding hypersomnia cases and typically present with 9 hours increases cardiovascular risk. The sudden-onset stupor with preservation of re- NOMAS study revealed an increased risk of car- sponses to stimuli.75 diovascular outcomes but not myocardial infarc- Hypersomnia treatment is important especially tion or nonvascular causes of death in patients during rehabilitation. A recent study demonstrated with increased daytime sleepiness as measured patients exhibiting hypersomnia symptoms in an by a modified . This acute rehabilitation unit were 10 times more likely increased risk in cardiovascular events persisted to be discharged to a nursing facility and had signif- after adjustment for covariates such as , icantly worse functional outcomes.76 Treatment of hypertension, and diabetes. The study further hypersomnia in stroke patients differs little from demonstrated a greater risk of mortality in exces- standard treatment of hypersomnia. Mainstays of sively sleepy women compared with men but no treatment involve use of amphetamines, , significant difference when evaluating race or , and in some cases, levodopa ethnicity.66 Long sleepers demonstrated that therapy. One study demonstrated that levodopa increased mortality correlated strongly with socio- and methylphenidate treatment improved arousal economic status.67 However, a study using data levels and poststroke outcome when administered from the Nurses’ Health Study failed to identify in an acute rehabilitation center over a 3-week an independent relationship between daytime period.77,78 Care should be taken when using am- sleepiness and long sleep time and increased car- phetamines and their derivatives in patients with diovascular morbidity and mortality when control- strokes given the potential for elevation of blood ling for confounding factors.68 pressure and heart rate (Table 1). The abnormality underlying the association be- tween hypersomnia and stroke is not well under- OTHER SLEEP DISORDERS AND STROKE stood, although several theories exist. The most (RESTLESS LEG SYNDROME, PERIODIC LIMB prominent hypothesis focuses on demonstrable MOVEMENTS IN SLEEP, PARASOMNIAS) increased incidence in obesity and diabetes seen in patients with hypersomnia. A study investigating Among the sleep disorders, there are 2 types of leg sleep in older women demonstrated decreased movements that are regularly diagnosed. Restless physical activity in patients with increased sleepi- leg syndrome (RLS) presents as a desire to move ness and fatigue.69 Long sleep is associated with the legs that worsens at night and at rest, is increased development of diabetes also, although partially relieved with movement, and worsens the underlying abnormality is unclear.68 Metabolic without movement.33 Periodic limb movements in syndrome, often seen in patients with obesity and sleep (PLMS) are defined as leg movements seen diabetes, results in increased proinflammatory cy- during that last 0.5 to 10 sec- tokines.70 Proinflammatory cytokines induce sleep onds and occur every 5 to 90 seconds, and at least as an evolutionary response to promote rest and 4 movements occur consecutively with at least an recovery from illness.71 Another confounder often 8 uV increase in amplitude from baseline as seen in associated with hypersomnia is depression, which the limb movement leads.79 Recent studies sug- increases mortality and risk of heart disease.72 A gest a relationship between sleep-related leg study investigating the relationship between movements and cardiovascular disease, including 8 Mims & Kirsch

Table 1 Stroke lesions and sleep disorders

Stroke Lesions Associated with Sleep Disorder Sleep apnea Frontal lobe (respiratory apraxia), pontine stroke (neurogenic hypoventilation), inferomedial posterior pons (apneustic respirations), medullary stroke (Ondine curse) Insomnia Supratentorial stroke (decreased NREM, TST, SE), right hemisphere decreased REM, left hemisphere decreased NREM, paramedian thalamus strokes decreased NREM, infratentorial strokes eliminate sleep spindles, K complexes, and/or vertex waves Hypersomnia Reticular activating system, bilateral thalamic lesions, lesions affecting left more than right and anterior more than posterior, paramedian thalamic infarcts (present with sudden onset stupor) RBD Brainstem infarcts

Abbreviations: SE, sleep efficiency; TST, total sleep time.

stroke, although the association of the leg move- Published case studies describe increased ments with possible vascular phenomena started PLMS and RLS incidence after stroke.89,90 Lee with Ekbom in the 1940s.80 and colleagues91 identified an incidence of 12% Several cohort studies, including the Wisconsin of stroke patients presenting with RLS. Most pa- Sleep Cohort Study, demonstrated significantly tients develop bilateral symptoms of RLS, but a increased incidence of hypertension and heart dis- third complain of RLS affecting the contralateral ease in those patients also reporting symptoms of side to the stroke. Conversely, a relationship has RLS. The Sleep Heart Health Study also reported been identified suggesting PLMS can increase an increase in cardiovascular disease and coro- the risk for stroke. A study done in 26 subjects nary artery disease in patients with RLS, but only with RLS control-matched to 241 patients without in RLS sufferers experiencing symptoms at least RLS demonstrated a greater volume of subcortical 16 times per month and with severe symptoms.81 lesions and cortical atrophy seen in the RLS In a cohort study on older men, a PLMS arousal in- group.92 The above studies provide anecdotal ev- dex exceeding 5 events per hour resulted in an idence that RLS/PLMS may increase the risk of increased risk for cardiovascular disease even af- stroke, especially in the basal ganglia, internal ter controlling for several comorbid conditions, capsule, or corona radiata. including age and BMI.82 According to a study per- formed by Siddiqui and colleagues,83 elevated Pathophysiology blood pressure following PLMS occurred in increasing and predictable ways based on type The pathophysiology resulting in correlation be- of PLMS. However, a few studies failed to find a tween sleep-related leg movements and cardio- correlation between hypertension and RLS, and vascular consequences such as stroke has yet to the MEMO study demonstrated an inverse rela- be identified definitively, but several theories exist. tionship between blood pressure and RLS.84–86 The most prominent theory linking leg movements One theory suggests the relationship between to cardiovascular risks revolves around hypofunc- sleep-related leg movements and cardiovascular tion of the A11 diencephalospinal pathway, which disease including stroke relates to increased sym- leads to increased sympathetic output to the pe- pathetic activation seen with arousals associated riphery via somatic muscle fibers.93 Typically, with PLMS. Increased sympathetic activation is increased sympathetic activity results in height- suggested by changes in pulse rate associated ened spinal sensory signaling via afferents from with PLMS. Interestingly, the pulse rate increase the muscle fibers back to the , but precedes the PLMS movement. A study by this activity is dampened by A11 innervation at Winkelman87 identified an increase in heart rate the dorsal horn. Theoretically, in RLS, the dopami- occurring 3 cardiac cycles before PLMS onset nergic hypofunctioning of the A11 innervation with peak at 4 cardiac cycles after PLMS onset. results in a positive feedback loop, causing A study by Sforza and colleagues88 found ac- increased signaling of afferents back to the spinal celerations in heart rate were highest when cord, which also causes heightened sympathetic PLMS induced a noticeable electroencephalo- activation leading to increased RLS symptoms. gram (EEG) microarousal. This theory is supported by lesion creation in this Sleep and Stroke 9 pathway in rats that results in a restlessness that adulthood, but estimated incidence of parasom- responds to pramipexole.94 The A11 diencephalo- nias remains approximately 4% in the adult popu- spinal pathway also links sympathetic activation to lation.97 Parasomnias may occur secondary to hypertension and increased risk of cardiovascular precipitating factors like medications ( consequences like heart disease and stroke. like ), stress, underlying sleep disorders, Comorbid conditions are also posited as a po- or . exhibits a tential pathophysiology linking sleep-related leg strong predilection in first-degree family members movements to increased cardiovascular morbidity with a 10-fold increase in incidence compared with and mortality. Winkelman and colleagues81 sug- the general population.98 Parasomnias may also gests that conditions such as and renal be correlated with stroke. failure may contribute to the association between pathophysiology consists of inter- cardiovascular risk and sleep-related leg move- ruption in sleep stages. Sleep stage shifting occurs ment. Many studies identified an association be- as a reorganization and transition of various tween sleep-related leg movements and OSA, a neuronal centers until one exerts prominence disorder that more clearly demonstrates increased and declares itself, and an arousal during this reor- cardiovascular risks, as described in an earlier ganization is hypothesized to increase complex section. Conversely, cardiovascular disease may motor and sensory behavior during sleep.99 increase the risk of sleep-related leg movements In REM sleep behavior disorder (RBD) specif- as seen in case studies. ically, brainstem lesions are strongly correlated Ferritin level and an iron panel should be a stan- with the development of enactment behav- dard part of an RLS evaluation, and iron supple- iors. In the study by Schenk and Mahowald100 mentation in patients with low ferritin with or described in later discussion, one patient devel- without low total iron-binding capacity saturation oped RBD in response to an acute brainstem can result in resolution of RLS symptoms. The stan- stroke and subsequently fractured her hip in the dard pharmacologic treatment for sleep-related leg intensive care unit (ICU) during hospitalization. movements continues to be dopamine agonists, Bilateral pontine tegmental lesions create RBD in with the highest level of recommendation encour- animal models. In a study performed in Hong aging the use of pramipexole 0.5 to 1.5 mg and ro- Kong, 22% of patients with a brainstem stroke ex- pinirole 1 to 4 mg. Levodopa can be used for hibited associated RBD and demonstrated lower patients with intermittent and predictable insti- brain volume involved in stroke compared with pa- gating factors exacerbating RLS symptoms. How- tients with stroke without RBD. Damage to pontine ever, levodopa is not recommended for use in glutaminergic and medullary GABAergic neurons patients needing chronic therapy due to the was implicated as the main abnormality resulting increased risk of augmentation. Gabapentin is in RBD in this study.101 increasingly used for RLS and PLMS with success, In one of the earliest published studies investi- especially in those with painful RLS or RLS related gating the relationship of parasomnia behavior in to diabetic neuropathy. Opioids can also be used ICU patients, parasomnias resulted from an acute for painful RLS. Newer therapy like rotigotine deliv- neurologic disorder in 28.5% (4/14) patients. Only ered over a 24-hour period via a transdermal patch 3 of 20 patients identified in the study exhibited has been shown to be more effective than prami- symptoms suggestive of NREM parasomnias; the pexole and ropinirole but also increases the risk of remaining parasomnias consisted of RBD.100 Of side effects and had a higher discontinuation the 4 parasomnia patients in this study who previ- rate.95 Gabapentin enacarbil, essentially a prodrug ously had a stroke, all were diagnosed with RBD. of gabapentin, is approved for use for RLS. Other Although RBD is the most commonly associated off-label treatments for RLS and PLMS include pre- parasomnia associated with stroke, other parasom- gabalin, , and clonidine, although nias have been described in association with the level of evidence is low.96 strokes. Case studies described visual hallucina- tions especially at associated with infarcts in the pontine tegmentum, midbrain, or para- Parasomnias medial thalamus.47 Increased dreaming or night- Parasomnias are undesirable physical events or mares and a syndrome resembling confusional experiences that occur during entry into sleep, arousal has been described following strokes in the within sleep, or during arousal from sleep.33 thalamus, temporal, parietal, and occipital lobes.102 Parasomnias include dream enactment behaviors, No clear evidence exists linking pre-existing sleepwalking, night terrors, and confusional parasomnias to the development of stroke; how- arousals, among others. Most parasomnias pre- ever, as mentioned previously in several sections, sent in children and adolescents and resolve by sleep disruption itself can result in increased 10 Mims & Kirsch

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