S l e e p a n d St ro k e

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

KEYWORDS
 Stroke  Sleep  Obstructive sleep apnea  RLS/PLMS  Parasomnias  Cerebrovascular accident
 Central sleep apnea  Insomnia  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
sleep.theclinics.com

a
Charlotte Medical Clinic, Carolinas HealthCare System, 1001 Blythe Boulevard, Suite 403, Charlotte, NC
28203, USA; b CHS Sleep Medicine, Carolinas HealthCare System, 1601 Abbey Place, Building 2, Suite 200, Char-
lotte, NC 28209, USA
* Corresponding author.
E-mail address: Douglas.Kirsch@carolinashealthcare.org

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.
2 Mims & Kirsch

The American Heart Association recommends been implicated in worsening dyslipidemia, oxida-
screening for OSA for stroke prevention and sug- tive stress, 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 Obstructive Sleep Apnea 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 stroke risk has yet to be identified, 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 (diabetes, 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 cytokines 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

OxidaƟve
stress

Endothelial
dysfuncƟon
and
inflammaƟon

InhibiƟon of
Insulin
lipoprotein Dyslipidemia Atherosclerosis Diabetes
resistance
lipase

Hypertension

Increased
sympatheƟc
acƟvaƟon

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 strokes.
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, fatigue, 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
despite higher minimum SaO2 levels observed in factors seen in stroke and sleep, including dyslipi-
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 sleep disorder, 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 medications.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, dementia 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 as reported 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 thalamus and brainstem, 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 Psychiatry 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 bedroom, 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 electroencephalography 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 medication interactions, and
Diagnosis and Treatment of Insomnia side effects.60 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. Actigraphy 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 sleep hygiene, including HYPERSOMNIA 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- depression 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 Epworth sleepiness scale. 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 obesity, 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, modafinil,
significant difference when evaluating race or methylphenidate, 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 polysomnography 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 spinal cord, 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 (hypnotics
consequences like heart disease and stroke. like zolpidem), stress, underlying sleep disorders,
Comorbid conditions are also posited as a po- or sleep deprivation. Sleepwalking 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 anemia and renal be correlated with stroke.
failure may contribute to the association between Parasomnia 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 dream 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, carbamazepine, 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 sleep onset 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

sympathetic output during sleep, thereby 5. Brooks D, Davis L, Vujovic-Zotovic N, et al. Sleep
increasing cardiovascular stress. disordered breathing in patients enrolled in an
For definitive diagnosis of parasomnias, poly- inpatient stroke rehabilitation program. Arch Phys
somnography may be required to distinguish Med Rehabil 2010;91(4):659–62.
between REM and NREM parasomnias and to 6. Marin JM, Carrizo SJ, Vicente E, et al. Long-term
evaluate for nocturnal seizures (which may require cardiovascular outcomes in men with obstructive
a full EEG montage). sleep apnea-hypopnea with or without treatment
Treatment of RBD typically consists of optimizing with continuous positive airway pressure: an obser-
the bedroom environment to reduce risk of injury vational study. Lancet 2005;365(9464):1046–53.
and treating underlying sleep disorders, such as 7. Young T, Finn L, Peppard PE, et al. Sleep disor-
OSA. Medication therapy for RBD includes clonaz- dered breathing and mortality: eighteen-year
epam at 0.5 mg to 2 mg an hour before bedtime. If follow-up of the Wisconsin sleep cohort. Sleep
clonazepam is not well-tolerated or contraindi- 2008;31(8):1071–8.
cated, such as in patients with dementia or gait dis- 8. Marshall NS, Wong KK, Cullen SR, et al. Sleep ap-
orders, melatonin is indicated. Melatonin is a safe nea and 20-year follow-up for all-cause mortality,
alternative to benzodiazepines that may also be stroke, and cancer incidence and mortality in the
effective for RBD treatment.103 Busselton Health Study cohort. J Clin Sleep Med
Pramipexole may also be used in this population 2014;10(4):355–62.
and has demonstrated effectiveness in some 9. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstruc-
studies, although contradictory studies exist as tive apnea-hypopnea and incident stroke: the
well. Case studies demonstrated effective treat- Sleep Heart Health Study. Am J Respir Crit Care
ment with the following medications, although evi- Med 2010;182(2):269–77.
dence is limited: zopiclone, benzodiazepines other 10. Meschia JF, Bushnell C, Boden-Albala B, et al.
than clonazepam, Yi-gan san, desipramine, cloza- Guidelines for the primary prevention of stroke: a
pine, carbamazepine, and sodium oxybate.104 statement for healthcare professionals from the
Treatment of parasomnias other than RBD is similar, American Heart Association/American Stroke As-
with clonazepam as the suggested initial treatment. sociation. Stroke 2014;45:3754–832.
11. Yaranov DM, Smyrlis A, Usatii N, et al. Effect of
obstructive sleep apnea on frequency of stroke in
SUMMARY
patients with atrial fibrillation. Am J Cardiol 2015;
Over the past decade, the importance of sleep dis- 115:461–5.
orders has grown within the medical community, 12. Williams SK, Ravenell J, Jean-Louis G, et al. Resis-
increasingly recognized as being related to many tant hypertension and sleep apnea: pathophysio-
medical conditions. This review has elucidated logic insights and strategic management. Curr
the bidirectional relationship of stroke with certain Diab Rep 2011;11:64–9.
sleep disorders, with further research necessary to 13. Rasche K, Keller T, Tautz B, et al. Obstructive sleep
better understand these correlations. Treatment of apnea and type 2 diabetes. Eur J Med Res 2010;
sleep disorders, whether causative of stroke or 15(Suppl 2):152–6.
caused by stroke, will likely improve sleep- 14. Tokuda F, Sando Y, Matsui H, et al. Serum levels of
related symptoms and may improve further stroke adipocytokines, adiponectin, and leptic, in patients
risk and long-term outcomes. with obstructive sleep apnea syndrome. Intern
Med 2008;47:1843–9.
REFERENCES 15. Jun J, Reinke C, Bedja D, et al. Effect of intermit-
tent hypoxia on atherosclerosis in apolipoprotein
1. Available at: http://www.cdc.gov/stroke/. Accessed E-deficient mice. Atherosclerosis 2010;209(2):
July 14, 2015. 381–6.
2. Young T, Palta M, Dempsey J, et al. The occur- 16. Savransky V, Nanayakkara A, Li J, et al. Chronic
rence of sleep-disordered breathing among intermittent hypoxia induces atherosclerosis. Am
middle-aged adults. N Engl J Med 1993;32: J Respir Crit Care Med 2007;175(12):1290–7.
1230–5. 17. Savransky V, Jun J, Li J, et al. Dyslipidemia and
3. Young T, Peppard PE, Gottlieb DJ, et al. The epide- atherosclerosis induced by chronic intermittent
miology of obstructive sleep apnea: a population hypoxia are attenuated by deficiency of stearoyl
health perspective. Am J Respir Crit Care Med coenzyme a desaturase. Circ Res 2008;103(10):
2002;165:1217–39. 1173–80.
4. Johnson KG, Johnson DC. Frequency of sleep ap- 18. Iesato K, Tatsumi K, Saibara T, et al. Decreased li-
nea in stroke and TIA patients: a meta-analysis. poprotein lipase in obstructive sleep apnea syn-
J Clin Sleep Med 2010;6:131–7. drome. Circ J 2007;71(8):1293–8.
 Sleep and Stroke 11

19. Drager LF, Polotsky VY, Lorenzi-Filho G, et al. Westchester (IL): American Academy of Sleep
Obstructive sleep apnea: an emerging risk factor Medicine; 2005.
for atherosclerosis. Chest 2011;140(2):534–42. 34. Phillips B, Mannino D. Correlates of sleep com-
20. Stocker R, Keaney JF Jr. Role of oxidative modifica- plaints in adults: the ARIC study. J Clin Sleep
tions in atherosclerosis. Physiol Rev 2004;84(4): Med 2005;1:277–83.
1381–478. 35. Morin CM, Bélanger L, LeBlanc M, et al. The natu-
21. Nadeem R, Molnar J, Madbouly EM, et al. Serum in- ral history of insomnia: a population-based 3-year
flammatory markers in obstructive sleep apnea: a longitudinal study. Arch Intern Med 2009;169(5):
meta-analysis. J Clin Sleep Med 2013;9(10):1003–12. 447–53.
22. Zamarron-Sanz C, Ricoy-Galbaldon J, Gude- 36. Chien KL, Chen PC, Hsu HC, et al. Habitual sleep
Sampedro F, et al. Plasma levels of vascular endo- duration and insomnia and the risk of cardiovascu-
thelial markers in obstructive sleep apnea. Arch lar events and all-cause death: report from a com-
Med Res 2006;37:552–5. munity based cohort. Sleep 2010;33:177–84.
23. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. 37. Leppavuori A, Pohjasvaara T, Vataja R, et al.
Elevation of plasma cytokines in disorders of Insomnia in ischemic stroke patients. Cerebrovasc
excessive daytime sleepiness: role of sleep distur- Dis 2002;14:90–7.
bance and obesity. J Clin Endocrinol Metab 1997; 38. Tang WK, Grace Lau C, Mok V, et al. Insomnia and
32:1313–6. health-related quality of life in stroke. Top Stroke
24. Jelic S, Lederer DJ, Adams T, et al. Vascular inflam- Rehabil 2015;22(3):201–7.
mation in obesity and sleep apnea. Circulation 39. Palomaki H, Berg A, Meririnne E, et al. Complaints
2010;121(8):1014–21. of poststroke insomnia and its treatment with mian-
25. Brown DL, Mowla A, McDermott M, et al. Ischemic serin. Cerebrovasc Dis 2003;15:56–62.
stroke subtype and presence of sleep-disordered 40. Bassetti C, Aldrich MS. Sleep apnea in acute cere-
breathing: the BASIC sleep apnea study. J Stroke brovascular diseases: final report on 128 patients.
Cerebrovasc Dis 2015;24(2):388–93. Sleep 1999;22:217–23.
26. Ferre A, Ribó M, Rodrı́guez-Luna D, et al. Strokes 41. Chen JC, Brunner RL, Ren H, et al. Sleep duration
and their relationship with sleep and sleep disor- and risk of ischemic stroke in postmenopausal
ders. Neurologia 2013;28(2):103–18. women. Stroke 2008;39:3185–92.
27. Parra O, Arboix A, Bechich S, et al. Time course of 42. Eguchi K, Pickering TG, Schwartz JE, et al. Short
sleep-related breathing disorders in first ever sleep duration as an independent predictor of
stroke or transient ischemic attack. Am J Respir cardiovascular events in Japanese patients with
Crit Care Med 2000;161:375–80. hypertension. Arch Intern Med 2008;168(20):
28. Rowat AM, Dennis MS, Wardlaw JM, et al. Central 2225–31.
periodic breathing observed during the acute 43. Eguchi K, Hoshide S, Ishikawa S, et al. Short
assessment is associated with an adverse prog- sleep duration and type 2 diabetes enhance the
nosis in conscious acute stroke patients. Cerebro- risk of cardiovascular events in hypertensive
vasc Dis 2006;21(5–6):340–7. patients. Diabetes Res Clin Pract 2012;98(3):
29. Rowat AM, Wardlaw JM, Dennis MS, et al. 518–23.
Abnormal breathing patterns in stroke: relationship 44. Wu MP, Lin HJ, Weng SF, et al. Insomnia subtypes
with location of acute stroke lesion and prior cere- and the subsequent risks of stroke: report from a
brovascular disease. J Neurol Neurosurg Psychia- nationally representative cohort. Stroke 2014;45:
try 2007;78(3):277–9. 1349–54.
30. Resmed. Available at: http://www.resmed.com/ 45. Huang WS, Tsai CH, Lin CL, et al. Nonapnea sleep
content/dam/resmed/global/documents/serve-hf/ disorders are associated with subsequent
Patient_SERVE-HF_FAQs.pdf. Accessed July 17, ischemic stroke risk: a nationwide, population-
2015. based, retrospective cohort study. Sleep Med
31. Elwood P, Hack M, Pickering J, et al. Sleep distur- 2013;14:1341–7.
bance, stroke, and heart disease events: evidence 46. Da Rocha PC, Barroso MT, Dantas AA, et al. Pre-
from the Caerphilly cohort. J Epidemiol Community dictive factors of subjective sleep quality and
Health 2006;60:69–73. insomnia complaint in patients with stroke: implica-
32. Aaronson JA, van Bennekom CA, Hofman WF, et al. tions for clinical practice. An Acad Bras Cienc
Obstructive sleep apnea is related to impaired 2013;85(3):1197–206.
cognitive and functional status after stroke. Sleep 47. Basetti CL. Sleep and stroke. Semin Neurol 2005;
2015;38(9):1431–7. 25:19–32.
33. American Academy of Sleep Medicine. The Inter- 48. Hermann DM, Bassetti CL. Sleep-disordered
national Classification of Sleep Disorders: diag- breathing and stroke. Curr Opin Neurol 2003;16:
nostic and coding manual. 2nd edition. 87–90.
12 Mims & Kirsch

49. Paffenbarger RS Jr, Lee IM, Leung R. Physical ac- 64. Arzt M, Young T, Peppard PE, et al. Disassociation
tivity and personal characteristics associated with of obstructive sleep apnea from hypersomnolence
depression and suicide in American college men. and obesity in patients with stroke. Stroke 2010;41:
Acta Psychiatr Scand Suppl 1994;377:16–22. e129–134.
50. Roth T, Ancoli-Israel S. Daytime consequences and 65. Watson NF, Badr MS, Belenky G, et al. Recommen-
correlates of insomnia in the United States: results ded amount of sleep for a healthy adult: a joint
of the 1991 national sleep foundation survey II. consensus statement of the American Academy
Sleep 1999;22:S354–8. of Sleep Medicine and Sleep Research Society.
51. Vgontzas AN, Liao D, Bixler EO, et al. Insomnia with J Clin Sleep Med 2015;11(6):591–2.
objective short sleep duration is associated with a 66. Boden-Albaba B, Roberts ET, Bazil C, et al. Day-
high risk for hypertension. Sleep 2009;32:491–7. time sleepiness and risk of stroke and vascular dis-
52. Friedman EM. Sleep quality, social well-being, ease. Circ Cardiovasc Qual Outcomes 2012;5:
gender, and inflammation: an integrative analysis 500–7.
in a national sample. Ann N Y Acad Sci 2011; 67. Patel SR. Social and demographic factors related
1231:23–34. to sleep duration. Sleep 2007;30(9):1077–8.
53. Gangwisch JE, Heymsfield SB, Boden-Albala B, 68. Gangwisch JE, Rexrode K, Forman JP, et al. Day-
et al. Short sleep duration as a risk factor for dia- time sleepiness and risk of coronary heart disease
betes incidence in a large US sample. Sleep and stroke: results from the Nurses’ Health Study II.
2007;30:1667–73. Sleep Med 2014;15:782–8.
54. Gasanov RL, Gitlevich TR, Lesnyak VN, et al. Struc- 69. Lambiase MJ, Gabriel KP, Kuller LH, et al. Tempo-
ture of nocturnal sleep in patients with cerebral ral relationships between physical activity and
insult. Neurosci Behav Physiol 1998;28:325–9. sleep in older women. Med Sci Sports Exerc
55. Korner E, Flooh E, Reinhart B, et al. Sleep alter- 2013;45:2362–8.
ations in ischemic stroke. Eur Neurol 1986; 70. Wisse BE. The inflammatory syndrome: the role of
25(Suppl 2):104–10. adipose-tissue cytokines in metabolic disorders
56. Freemon FR, Salinas-Garcia RF, Ward JW, et al. linked to obesity. J Am Soc Nephrol 2004;15:
Sleep patterns in a patient with a brain stem infarc- 2792–800.
tion involving the raphe nucleus. Electroencepha- 71. Vgontzas AN, Chrousos GP. Sleep, the
logr Clin Neurophysiol 1974;36:657–60. hypothalamic-pituitary-adrenal axis, and cytokines:
57. Markand ON, Dyken ML. Sleep abnormalities in multiple interactions and disturbances in sleep dis-
patients with brain stem lesions. Neurology 1976; orders. Endocrinol Metab Clin North Am 2002;31:
26:769–76. 15–36.
58. Valldeoriola F, Santamaria J, Graus F, et al. 72. Cuijpers P, Smit F. Excess mortality in depression: a
Absence of REM sleep, altered NREM sleep, and meta-analysis of community studies. J Affect Dis-
supranuclear horizontal gaze palsy caused by a ord 2002;72:227–36.
lesion of the pontine tegmentum. Sleep 1993;16: 73. Patel SR, Malhotra A, Gottlieb DJ, et al. Correlates
184–8. of long sleep duration. Sleep 2006;29:881–9.
59. Vock J, Achermann P, Bischof M, et al. Evoluation 74. Passouant P, Cadilhac J. Physiopathology of
of sleep and sleep EEG after hemispheric stroke. hypersomnias. Rev Neurol (Paris) 1967;116:
J Sleep Res 2002;11(4):331–8. 585–629.
60. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical 75. Catsman-Berrevoets CE, von Harskamp F.
guideline for the evaluation and management of Compulsive pre-sleep behavior and apathy due
chronic insomnia in adults. J Clin Sleep Med to bilateral thalamic stroke: response to bromocrip-
2008;4(5):487–504. tine. Neurology 1988;38:647–9.
61. Lee SY, Baek YH, Park SU, et al. Intradermal 76. Harris AL, Elder J, Schiff ND, et al. Post-stroke
acupuncture on shen-men and nei-kuan acupoints apathy and hypersomnia lead to worse outcomes
improves insomnia in stroke patients by reducing from acute rehabilitation. Transl Stroke Res 2014;
the sympathetic nervous system activity: a ran- 5(2):292–300.
domized clinical trial. Am J Chin Med 2009;37: 77. Scheidtmann K, Fries W, Müller F, et al. Effect of
1013–21. levodopa in combination with physiotherapy on
62. Pech M, O’kearney R. A randomized controlled trial functional motor recovery after stroke: a prospec-
of problem-solving therapy compared to cognitive tive, randomized, double-blind study. Lancet
therapy for the treatment of insomnia in adults. 2001;358:787–90.
Sleep 2013;36:739–49. 78. Grade C, Redford B, Chrostowski J, et al. Methyl-
63. Young TB. Epidemiology of daytime sleepiness: phenidate in poststroke recovery: a double-blind,
definitions, symptomatology, and prevalence. placebo-controlled study. Arch Phys Med Rehabil
J Clin Psychiatry 2004;65(Suppl 16):12–6. 1998;79:1047–50.
 Sleep and Stroke 13

79. Iber C, Ancoli-Israel S, Chesson A, et al. The AASM results point to the need for more sophisticated
manual for the scoring of sleep and associated studies. Open Neurol J 2010;4:73–7.
events: rules, terminology and technical specifica- 93. Walters A, Rye DB. Review of the relationship of
tions. Westchester (IL): American Academy of restless leg syndrome and periodic limb move-
Sleep Medicine; 2007. ments in sleep to hypertension, heart disease,
80. Ekbom KA. Restless leg syndrome. Neurology and stroke. Sleep 2009;32(5):589–97.
1960;10:868–73. 94. Ondo WG, He Y, Rajasekaran S, et al. Clinical cor-
81. Winkelman JW, Shahar E, Sharief I, et al. Associa- relates of 6-hydroxydopamine injections into A11
tions of restless leg syndrome and cardiovascular dopaminergic neurons in rats: a possible model
disease in the Sleep Heart Health Study. Neurology for restless leg syndrome. Mov Disord 2000;15:
2005;64:1920–4. 154–8.
82. Koo BB, Blackwell T, Ancoli-Israel S, et al. Associ- 95. Sun Y, van Valkenhoef G, Morel T. A mixed
ation of incident cardiovascular disease with peri- treatment comparison of gabapentin enacarbil,
odic limb movements during sleep in older men; pramipexole, ropinirole, and rotigotine in
outcomes of sleep disorders in older men (MrOS) moderate-to-severe RLS. Curr Med Res Opin
study. Circulation 2011;124(11):1223–31. 2014;30(11):2267–78.
83. Siddiqui F, Strus J, Ming X, et al. Rise of blood 96. Aurora RN, Kristo DA, Bista SR, et al. The treatment
pressure with periodic limb movements in sleep of restless leg syndrome and periodic limb move-
and wakefulness. Clin Neurophysiol 2007;118: ment disorder in adults—an update for 2012: prac-
1923–30. tice parameters with an evidence based systemic
84. Ulfberg J, Nyström B, Carter N, et al. Prevalence of review and meta-analysis. Sleep 2012;35(8):
restless leg syndrome among men aged 18 to 64 1039–62.
years: an association with somatic disease and 97. Ohayon MM, Guilleminault C, Priest RG. Night ter-
neuropsychiatric symptoms. Mov Disord 2001;16: rors, sleep walking, and confusional arousals in
1159–63. the general population: their frequency and rela-
85. Hogl B, Kiechl S, Willeit J, et al. Restless leg syn- tionship to other sleep and mental disorders.
drome: a community-based study of prevalence, J Clin Psychiatry 1999;60(4):268–76.
severity, and risk factors. Neurology 2005;64: 98. Kales A, Soldatos CR, Bixler EO, et al. Hereditary
1920–4. factors in sleepwalking and night terrors. Br J Psy-
86. Rothdach AJ, Trenkwalder C, Haberstock J, et al. chiatry 1980;137:111–8.
Prevalence and risk factors of RLS in an elderly 99. Mahowald MW, Ettinger MG. Things that go bump
population. Neurology 2000;54:1064–8. in the night: the parasomnias revisited. J Clin Neu-
87. Winkelman JW. The evoked heart rate response to rophysiol 1990;7(1):119–43.
periodic leg movements of sleep. Sleep 1999;22: 100. Schenk CH, Mahowald W. Injurious sleep behavior
575–80. disorders (parasomnias) affecting patients on
88. Sforza E, Nicolas A, Lavigne G, et al. EEG and car- intensive care units. Intensive Care Med 1991;17:
diac activation during periodic leg movements in 219–24.
sleep: support for a hierarchy of arousal re- 101. Tang WK, Hermann DM, Chen YK, et al. Brainstem
sponses. Neurology 1999;52:786–91. infarcts predict REM sleep behavior disorder in
89. Kang SY, Sohn YH, Lee IK, et al. Unilateral periodic acute ischemic stroke. BMC Neurol 2014;14:88.
limb movement in sleep after supratentorial cere- 102. Boller F, Wright DG, Cavalieri R, et al. Paroxysmal
bral infarction. Parkinsonism Relat Disord 2004; “nightmares”. Sequel of stroke responsiveness to
10:429–31. diphenylhydantoin. Neurology 1975;25:1026–8.
90. Lee JS, Lee PH, Huh K, et al. Periodic limb move- 103. Boeve BF, Silber MH, Ferman TJ. Melatonin for
ments in sleep after a small subcortical infarct. Mov treatment of REM sleep behavior disorder in neuro-
Disord 2005;20:260–1. logic disorders: results in 14 patients. Sleep Med
91. Lee SJ, Kim JS, Song IU, et al. Poststroke restless 2003;4(4):281–4.
legs syndrome and lesion location: anatomical 104. Aurora RN, Zak RS, Maganti RK, et al. Best prac-
considerations. Mov Disord 2009;24:77–84. tice guide for the treatment of REM sleep
92. Walters AS, Moussouttas M, Siddiqui F, et al. Prev- behavior disorder (RBD). J Clin Sleep Med
alence of stroke in restless legs syndrome: initial 2010;6(1):85–95.