revue neurologique 179 (2023) 782–792

Available online at

ScienceDirect
www.sciencedirect.com

Scientific day of the French Neurology Society – Sleep and Neurology

The multifaceted aspects of sleep and sleep-wake

disorders following stroke

S. Baillieul a,1,*, C. Denis b,1, L. Barateau b,c, C. Arquizan d,e, O. Detante f,

J.-L. Pépin a, Y. Dauvilliers b,c,2, R. Tamisier a,2
a
Université Grenoble Alpes, Inserm, U1300, CHU Grenoble Alpes, Service Universitaire de Pneumologie Physiologie,
38000 Grenoble, France
b
National Reference Centre for Orphan Diseases Narcolepsy Rare Hypersomnias, Sleep Disorders Unit, Department of
Neurology, CHU de Montpellier, University of Montpellier, Montpellier, France
c
Institute for Neurosciences of Montpellier (INM), University of Montpellier, Inserm, Montpellier, France
d
Department of Neurology, Hôpital Gui-de-Chauliac, Montpellier, France
e
Inserm U1266, Paris, France
f
Neurology Department, Grenoble Alpes University Hospital, Grenoble, France

info article abstract

Article history: Sleep-wake disorders (SWD) are acknowledged risk factors for both ischemic stroke and
Received 31 July 2023 poor cardiovascular and functional outcome after stroke. SWD are frequent following
Accepted 1st August 2023 stroke, with sleep apnea (SA) being the most frequent SWD affecting more than half of
Available online 21 August 2023 stroke survivors. While sleep disturbances and SWD are frequently reported in the acute
phase, they may persist in the chronic phase after an ischemic stroke. Despite the frequency
Keywords: and risk associated with SWD following stroke, screening for SWD remains rare in the
Stroke clinical setting, due to challenges in the assessment of post-stroke SWD, uncertainty
Sleep regarding the optimal timing for their diagnosis, and a lack of clear treatment guidelines
Sleep apnea (i.e., when to treat and the optimal treatment strategy). However, little evidence support the
Insomnia feasibility of SWD treatment even in the acute phase of stroke and its favorable effect on
Recovery long-term cardiovascular and functional outcomes. Thus, sleep health recommendations
Secondary prevention and SWD treatment should be systematically embedded in secondary stroke prevention
strategy. We therefore propose that the management of SWD associated with stroke should
rely on a multidisciplinary approach, with an integrated diagnostic, treatment, and follow-
up strategy. The challenges in the field are to improve post-stroke SWD diagnosis, prognosis
and treatment, through a better appraisal of their pathophysiology and temporal evolution.
# 2023 Elsevier Masson SAS. All rights reserved.

* Corresponding author. Laboratoire du Sommeil - CHU Grenoble Alpes, Hôpital Nord, SHU Pneumologie Physiologie, CS 10217, 38043
Grenoble Cedex 09, France.
E-mail address: sbaillieul@chu-grenoble.fr (S. Baillieul).
1
Share co-first authorship.
2
Share co-last authorship.
https://doi.org/10.1016/j.neurol.2023.08.004
0035-3787/# 2023 Elsevier Masson SAS. All rights reserved.
 revue neurologique 179 (2023) 782–792 783

1. Sleep and stroke: united for better or worse
Stroke affects almost 80 million patients worldwide, and is the
leading cause of acquired disability in adults, and the second
leading cause of death [1]. Among all strokes, ischemic stroke
is the most common subtype accounting for up to 88% [2].
Sleep, a physiological and homeostatic activity which occu-
pies a third of every human life, has recently been included in
the essential cardiovascular health risk factors that can be
mitigated via lifestyle changes or interventions in primary
prevention efforts [3,4].
Sleep and stroke are tightly linked. On the one hand, as a risk
factor for stroke and on the other hand as a cause of sleep
impairment. Specific sleep patterns and wake impairments may,
indeed, increase stroke risk. In the large international INTERS-
TROKE case-control study (n = 4496 participants), sleep distur-
bance symptoms were associated with a graded increased risk of
stroke [5]. Long sleep duration in the general population is
associated with the presence of white matter hypersignals ( 9 h
of sleep per night) [6] and an increased stroke risk (> 7 h of sleep
per night), with a dose-response relationship for each additional
hour of sleep [7,8]. Long sleep has recently been associated with
greater odds of carotid plaque presence and larger total plaque
area [9]. A recent meta-analysis showed that short sleep duration
was also linked to an increased risk of stroke incidence and
stroke mortality [10]. Recently, sleep irregularity, both in
duration and timing, was shown to be a risk marker for poor
cardiovascular health [11]. Moreover, sleep disorders such as
insomnia or obstructive sleep apnea may increase stroke risk
[12]. In the seminal study by Yaggi et al. [13], untreated
obstructive sleep apnea was associated with a doubling in
stroke risk, even after adjustment for major cardiovascular risk
factors. Excessive daytime sleepiness (EDS), defined as the
inability to stay awake during the normal wake period of the day
[14,15] is associated with the occurrence of cardiovascular
events, and this association persists even after adjustment for
traditional cardiovascular risk factors [16].
Stroke may directly influence sleep. Poor sleep quality [17],
as well as sleep disturbances are frequent patients’
complaints following stroke [12]. Initially considered as
transient, sleep disturbances may persist even at a chronic
delay following stroke [18], and negatively influence stroke
prognosis, being associated with an increased risk of
recurrent cardiovascular and cerebrovascular events
[12,19]. Moreover, sleep disturbances may also negatively
impair functional outcome [12,20,21], as sleep is considered a
‘‘plasticity state’’ in the recovery process following ischemic
stroke [22] (Fig. 1).
In this review, we will present the specificities of sleep
disturbances and sleep-wake disorders following ischemic
stroke, highlighting a need for their proper management in
secondary prevention, and to improve recovery and stroke
survivors’ quality of life. Clinical and research perspectives
will be finally proposed.

Fig. 1 – Health trajectories of patients with post-stroke SWD and impact of treatment. Sleep-wake disorders (SWD) are
acknowledged risk factors for stroke. SWD are also frequent post-stroke and are associated with poorer cardiovascular
morbimortality and functional outcome, through impairments in sleep micro- and macro-architecture and the specific
pathophysiological repercussions of SWD. Treatment of SWD in secondary prevention may improve stroke outcome,
including improvements in patients’ quality of life through improvement in sleep architecture and sleep efficiency.
Hypersomnolence covers hypersomnia and/or excessive daytime sleepiness. SWD: sleep-wake disorders; SA: sleep apnea;
RLS: restless legs syndrome.
784 revue neurologique 179 (2023) 782–792
2. Objectively measured sleep after stroke
As sleep is one of the brain’s function, stroke may directly
impact sleep, and it has been suggested that post-stroke sleep
architecture changes may represent a marker of brain damage
due to stroke [23].
In a systematic review and meta-analysis (9 studies),
Baglioni et al. [24] highlighted poorer sleep quality in stroke
patients compared to controls in the early recovery phase post-
stroke, with lower sleep efficiency and stability, shorter total
sleep time and more wake after sleep onset (WASO). This was
objectivated in stroke patients by more time spent in stage 1,
and less time in stage 2 and stage 3 sleep, with no difference for
rapid eye movement (REM) sleep. In a cohort study (SAS-Care
1), matched with a non-stroke population randomly selected
from the HypnoLaus cohort [25], Miano et al. [23] showed severe
sleep disruption in the acute phase of stroke, with a significant
improvement of sleep quality over the three months after
stroke, without normalization of sleep architecture. In this
study, sleep efficiency and REM sleep were particularly
impaired compared to matched controls, with a relative
preservation of non-REM (NREM) sleep. A recent study also
reported that the decrease in total sleep time and in REM sleep
were also associated with poorer functional outcome in
patients following moderate to severe stroke [21]. Interestingly,
Gottlieb et al. [26] showed, in a cross-sectional study conducted
in chronic stroke patients [n = 23, mean  SD delay between
stroke and polysomnography (PSG) = 4.1  0.9 years] and
matched controls (n = 16), that stroke patients had an increased
time in stages 1 and 2 sleep, reduced slow-wave sleep time, and
a higher arousal index, but no difference in total sleep time or
wake after sleep onset, when compared to controls. There was
no difference in ipsi- versus contra-lesionally scored sleep
architecture. If 57% of stroke patients presented undiagnosed
moderate-severe sleep apnea (SA), controlling for SA severity
did not dampen the importance of sleep architectural
differences between groups. Thus, ischemic stroke may
directly impact sleep macro-architecture from the acute to
the chronic phase. The influence of sleep disorders, as well as a
more precise appraisal of the temporal evolution of sleep post-
stroke should be precised in larger cohorts.
3. Sleep disturbances following stroke and
their impact on stroke outcome (Fig. 1)
3.1. Sleep apnea
SA is one of the most common chronic diseases, affecting
nearly a billion people worldwide [27]. SA is a sleep-related
breathing disorder, characterized by recurrent complete
(apnea) or incomplete (hypopnea) cessation of airflow during
sleep, and covers two distinct phenotypes: central SA related
to breathing instability and obstructive SA related to upper
airway collapsibility. Obstructive SA, the most frequent SA
phenotype, is considered a major public health problem
because of its individual, societal and economic consequences
[28]. Obstructive SA is an acknowledged cardio-metabolic risk
factor [29], and severe obstructive SA (apnea-hypopnea index
[AHI] > 30/h) is associated with a doubling of ischemic stroke
risk [12].
SA is common in the aftermath of stroke, found in over
70% of patients (mild-to-severe SA, defined by an AHI > 5/
h), a frequency four times higher than that found in the
general population [27,30,31]. Severe SA (AHI > 30/h) is
diagnosed in 30% of post-stroke patients. [30,31] Since
stroke severity, etiology, and stroke lesion location gene-
rally do not correlate with the severity or phenotype of post-
stroke SA [32–34], SA might be considered to reflect a pre-
existing condition. Moreover, the stable prevalence of the
obstructive SA phenotype at three months post-stroke
supports the hypothesis of pre-existence of SA [34].
Recently, a longitudinal cohort study confirmed the stabi-
lity of SA severity over the first year post-stroke [35]. If the
correlation between stroke lesion location and SA severity
and phenotypes remains unclear [12,36], ischemic stroke
lesions in critical areas regulating upper airway patency or
breathing effort may generate de novo SA [36,37]. Some
reports suggest that stroke lesions affecting the central
autonomic network at the supratentorial level and the
medulla or the cerebellum at the infratentorial level may be
linked to central SA [32,36,38].
Since SA following stroke is highly frequent and associated
with poorer functional prognosis and increased risk of
cardiovascular morbidity and mortality when untreated,
international recommendations support the development of
care pathways for the screening, diagnosis and treatment of
SA associated with stroke [12,39]. However, a recent study
showed that the Barthel Index, and the modified Rankin score
were similar at baseline and three months post-stroke in
different groups as function of severity of obstructive SA.
Moreover, in patients with worse clinical outcomes at three
months post-stroke, mean nocturnal oxygen saturation was
lower, whereas there was no association with the AHI [21].
Nevertheless, SA remains largely underdiagnosed and untrea-
ted due to technical and organizational barriers, particularly in
the acute phase of stroke [40,41].
3.1.1. Screening for sleep apnea following stroke: clinical
features and questionnaires
The search for SA symptoms should be an integral part of the
post-stroke patient care pathway [36,42]. From a pathophy-
siological point of view, it is now accepted that, in the majority
of cases, SA pre-exists the stroke [36]. Thus, SA should be
suspected in patients with a history of snoring or apnea
observed by relatives. Fatigue and excessive daytime sleepi-
ness, the cardinal symptoms of obstructive SA in stroke-free
patients, are neither sufficiently specific nor sufficiently
sensitive for the diagnosis of post-stroke SA [43]. Regarding
questionnaires, a systematic review concluded that most
questionnaires for screening obstructive SA syndrome have
high sensitivity but low specificity in stroke patients [44].
Because of their low overall predictive value, current ques-
tionnaires cannot be recommended as sufficiently accurate
screening tools for SA associated with stroke [44]. Thus, in
view of the high frequency of SA and the evidence that
treatment of SA can benefit stroke patients (see below), SA
screening should be offered to all patients who have presented
with ischemic stroke [36].
 revue neurologique 179 (2023) 782–792
3.1.2. Screening and diagnosis of sleep apnea: sleep recordings
Although currently under study, the usefulness of pulse
oximetry [45], easy to implement in neurovascular intensive
care units in the acute phase of stroke, has not yet been
validated to facilitate screening for SA [44]. The American
Academy of Sleep Medicine recommends PSG recordings to
diagnose post-stroke SA [46]. Beyond SA diagnosis, PSG
recordings are also useful to understand the pathophysiolo-
gical repercussions of SA: oxygen desaturations (intermittent
hypoxia), arousals (sleep fragmentation), and pulse wave
amplitude attenuation (sympathetic activity). However, PSG
recordings are often not available outside specialized centers.
Ventilatory polygraphy [47] represents an interesting alterna-
tive in post-stroke patients for assessing both the presence
and severity of SA.
The optimal timing for the diagnosis and management of
SA after stroke has yet to be established, but current European
recommendations call for SA to be detected and treated in the
acute phase of stroke [12]. From a practical point of view [36],
patients could benefit from ventilatory polygraphy recording
in the days following stroke, ideally before discharge from the
neurovascular intensive care unit. Patients with comorbidities
(i.e., suspected comorbid sleep disorder other than SA, chronic
obstructive pulmonary disease or heart failure) that may
render interpretation of ventilatory polygraphy difficult
should benefit from PSG recording. This strategy could
contribute to the early diagnosis of moderate-to-severe SA
in stroke patients, and to the rapid initiation of SA treatment.
3.1.3. Integrated management strategy for stroke-associated
sleep apnea and its impact on patient prognosis
Untreated SA in the aftermath of stroke is associated with a
poor prognosis, both in terms of functional recovery [48,49],
and cardiovascular morbidity and mortality [36], exposing
patients to the risk of recurrent stroke [12,36,50].
As part of secondary prevention strategies in the aftermath
of stroke, treatment of SA should therefore be integrated with
aggressive cardio-metabolic risk reduction strategies [36].
Continuous positive airway pressure (CPAP), the standard
treatment for SA, is thus recommended for post-stroke
patients [12]. Based on knowledge gained from the manage-
ment of SA in the general population, education and lifestyle
interventions (physical activity, diet) should also be integrated
into the long-term management of SA associated with stroke.
The effectiveness of CPAP depends on patient compliance.
In stroke patients, data from the literature demonstrate that
CPAP treatment is possible with acceptable compliance ( 4 h/
night) both in the acute phase [51,52] and subacute phase post-
stroke [51,53]. Cohort studies show, however, that long-term
compliance remains moderate (39% at 5 years) [53]. Factors
favoring compliance include less impairment of cognitive and
motor functions, good family support and low levels of
daytime fatigue. On the other hand, female gender, age,
smoking, depressive symptoms, subjective and comorbid
sleep disorders and discomfort with CPAP masks are reco-
gnized risk factors for poor compliance [36]. Interestingly,
stroke patients with good initial compliance tend to continue
their treatment over the long-term [53]. This suggests that
allocating resources to improve compliance at the initiation of
CPAP may improve the use and ultimately the effect of
785
treatment over longer periods. These interventions would not
be possible without the use of telemonitoring and the help and
involvement of homecare providers [54], an essential link in
the management of SA. The results of studies available to date
suggest the efficacy of CPAP treatment in post-stroke
secondary prevention in reducing the risk of stroke recurrence
and cardiovascular morbidity and mortality [12,36]. With
regard to functional recovery, the meta-analysis by Brill et al.
[51] (10 randomized clinical trials, 564 post-stroke patients)
shows an overall functional improvement with CPAP. The
benefits would be even greater if CPAP was started early after
the stroke, particularly for recovery of cognitive performance
[55].
Adaptive servo-ventilation (ASV) devices are specifically
designed to conjointly treat central and obstructive SA. The
beneficial effect of ASV on the evolution of the lesion volume
and on clinical stroke outcomes is currently being tested
acutely after stroke in a multicenter European study [Early
Sleep Apnoea Treatment in Stroke (eSATIS), NCT02554487]
[56].
3.2. Insomnia
3.2.1. Epidemiology of post-stroke insomnia and its impact on
post-stroke outcome
Insomnia is a highly frequent condition, occurring in up to a
third of the adult population worldwide [57,58]. Insomnia is
defined as a sleep continuity disturbance associated with
daytime complaints [58]. The role of insomnia as a risk factor
for cardiovascular and metabolic comorbidities has recently
been described, especially when associated with objective
short sleep duration [59].
If stroke can lead to de novo insomnia [60,61], data
regarding the exact prevalence of post-stroke insomnia lacks
reproducible assessment post-stroke. In the most recent
European guidelines [12], eight studies investigating insomnia
prevalence post-stroke have been identified, with prevalence
values ranging between 27–60%, depending on the delay
between stroke and insomnia assessment, as well as the tool
used to diagnose insomnia (mostly questionnaires and the
application of diagnostic criteria). The evolution of insomnia
over time remains uncertain, however, insomnia was found in
30–49% of patients 12–18 months post-stroke [12]. In the most
recent prospective, questionnaire-based cohort study to date,
insomnia (Insomnia Severity Index [ISI] sum score > 10) was
reported by 28.2% and 20.8% of the 437 included ischemic
stroke patients within seven days and at two years following
stroke, respectively [18]. A recent study also reported that
insomnia was also associated with poorer functional outcome
following stroke [21]. In a study combining PSG and the
multiple sleep latency test (MSLT), community-dwelling
chronic (> 12 months) right-hemispheric stroke patients
(n = 19) presented poorer sleep with longer sleep latencies,
lower sleep efficiency, greater wake after sleep onset, and
showed greater high-frequency power during NREM sleep
when compared to sex- and age-matched controls (n = 21) [62].
Moreover, MSLT revealed greater alertness in stroke patients
[62].
Several determinants of post-stroke insomnia have been
identified, including female gender, poorer functional out-
786 revue neurologique 179 (2023) 782–792
come and depression [12]. Recently, a resting-state functional
magnetic resonance imaging study conducted in 27 stroke
patients diagnosed with insomnia showed abnormal local
activities in multiple brain regions, including the visual
processing-related cortex, sensorimotor cortex, and some
default-mode network regions [63].
Beyond its significant impact on quality of life and its
association with depression [64,65], insomnia has a significant
impact on stroke outcome. In a prospective multicentric
cohort study of 1062 first-time stroke patients, insomnia (as
defined by DSM-IV criteria, 38.4% of patients) was associated
with increased mortality (hazard ratio: 1.66, 95% CI: 1.10–2.48)
during the six years of follow-up, even after adjusting for all
confounders [66]. Joa et al. [67], in a prospective cohort study of
280 patients assessed one month after stroke, showed that
insomnia (as defined by DSM-IV criteria, 26.9% of patients) was
associated with poorer functional recovery, as assessed by the
Berg balance scale.
3.2.2. Treatment of insomnia and its impact on stroke
outcome
The management of post-stroke insomnia has been poorly
studied. In a randomized controlled study including 100
ischemic stroke patients, Palomaki et al. [64] showed a
significant improvement of values of the insomnia score after
two months in the group treated by mianserin (60 mg/day)
when compared to placebo, but no difference at six, 12 and
18 months. The authors suggest that mianserin had a
beneficial influence on the acceleration of recovery from
symptoms of insomnia post-stroke.
The efficacy of digital cognitive behavioral therapy for
insomnia to improve sleep after stroke has recently been
tested [68]. In this randomized controlled, parallel groups
study, including 84 community-dwelling stroke patients
(mean  1SD=5.5  5.0 years post-stroke), eight weeks of
digital cognitive behavioral therapy induced significant
improvements in Sleep Condition Indicator-8 when compared
with control. Notably, 16 participants (13 in the intervention
group, 3 controls) withdrew without completing the post-
intervention assessment. However, this study confirms the
feasibility of such interventions in selected populations. No
study to date has evaluated the impact of post-stroke
insomnia treatment on stroke outcome.
3.3. Restless legs syndrome and periodic limb movements
3.3.1. Restless legs syndrome and periodic limb movements as
a risk factor for stroke and cerebrovascular disease
Restless legs syndrome (RLS) or Willis–Ekbom syndrome is a
sleep-related sensorimotor disorder characterized by a dis-
comfort and an urge to move the lower limbs, worsened by
immobility, improved by movement, and predominant in the
evening. The symptoms may also concern the upper limbs.
The diagnosis is made clinically, based on the four criteria
above, and the absence of any other cause that could explain
the symptoms [69]. RLS can be responsible for significant
insomnia, and is also associated with reduced quality of life
[70], depressive symptoms and even suicidal thoughts [71].
The pathophysiology of RLS is complex and not yet fully
understood. Genetic factors may favor the onset of RLS; a
disorder of iron metabolism with intracerebral iron deficiency,
a dysregulation of dopaminergic pathways, a hyperglutama-
tergic state and abnormalities in the adenosine pathway are
also implicated [72].
Periodic limb movements (PLM) are repetitive involuntary
movements of the lower limbs, or sometimes of four limbs,
which occur during sleep. These stereotyped movements are
described as extension of the big toe, dorsiflexion of the foot
and flexion of the hip. Diagnosis of PLM is based on PSG, with
detection on the electromyogram of the forelegs of a series of at
least four repetitive movements, lasting 0.5 to 10 seconds and
spaced 4 to 90 seconds apart [73]. A PLM index greater than 15/
hour is considered pathological, as defined by the International
Classification of Sleep Disorders (ICSD-TR), revised third
edition. PLM may be asymptomatic and discovered incidentally
or may be associated with RLS (25% of cases). PLM can lead to
autonomic activation, increasing heart rate and blood pressure
[74,75]. They may also be associated with micro-arousals and
arousals leading to insomnia. Drowsiness is possible, but not
significant compared to the decrease in sleep duration [72].
Prevalence of RLS in European and North American popu-
lations ranges from 5 to 13% [76]. RLS is also associated with
metabolic pathologies (such as diabetes, dyslipidemia, iron
deficiency), arterial hypertension, renal insufficiency, and some
medications (neuroleptics and antidepressants in particular). In
the general population, a PLM index above 15/hour is found in
28.6% of individuals and is associated with male gender, age,
higher body mass index (BMI) and high blood pressure [77].
The association between nocturnal motor disorders and
the risk of cardiovascular or cerebrovascular disease is
controversial. RLS was associated with all-cause mortality,
but not with stroke after adjustment for potential confounding
factors [12]. On the other hand, in patients with end-stage
chronic renal failure, RLS was associated with stroke [60]. The
presence of PLM in the general population is associated with
an increased prevalence of stroke in a meta-analysis of 9800
patients [78]. They also seem to be associated with cerebral
small vessel disease, with an increased prevalence of white
matter hypersignals, silent lacunar infarcts and widening of
Virchow Robin spaces in patients with a PLM index > 15/hour
[79,80]. The impact of RLS or PLM treatment on vascular risk or
mortality is unknown.
3.3.2. Epidemiology of post-stroke PLM or RLS
The prevalence of RLS after stroke or high-risk transient
ischemic attack varies between studies, ranging from 7.7% to
24% of patients [12]. RLS was generally associated with
hypertension, dyslipidemia and female gender, but the
prevalence of RLS in post-stroke period remains higher than
that in controls even after adjustment [81]. Between 2% and
3.3% of patients develop RLS after a stroke, most often
unilaterally and contralaterally to the brain lesion [82,83].
Subcortical locations (basal ganglia, corona radiata, thalamus
and internal capsule) are mostly associated with the deve-
lopment of de novo RLS [82]. The time of onset varies from
study to study, ranging from 2 days to 1 week following the
stroke [83]. In patients with RLS diagnosed prior to stroke, deep
cerebral infarcts or predominantly hemorrhagic strokes are
predominant. RLS was shown to be one of the factors, after
arterial hypertension, most strongly favoring this topography
 revue neurologique 179 (2023) 782–792
of lesions [84]. Patients with PLM are also more prone to
present white matter hypersignals, even after adjustment for
the usual vascular risk factors [85].
Mean PLM index and the proportion of patients with a PLM
index > 15/h are comparable between stroke patients and
controls, both in the early phase and at 3 months following the
cerebrovascular event [86]. De novo PLM onset after stroke has
been poorly studied so far. As the diagnosis of PLM relies on
polysomnography, a pre-stroke recording would be manda-
tory to ascertain the presence or absence of pre-stroke PLM.
3.3.3. Impact of PLM and RLS on stroke outcomes
The literature regarding the impact of RLS on post-stroke
outcome is scarce. A study on 96 ischemic stroke patients
showed an alteration in sleep quality and a greater disability
(Barthel index and the modified Rankin score) in patients with
RLS at 3 and 12 months post-stroke compared to those free of
RLS [87]. There was no difference in the risk of stroke recurrence.
In another study of 61 ischemic stroke patients, RLS 15 days
after ischemic stroke was more frequent in patients with poorer
functional outcome, as assessed by modified Rankin Scale [21].
Finally, a study on 94 patients with ischemic stroke or TIA
showed a greater deterioration in post-stroke quality of life in
patients with RLS, and a higher frequency of depressive
symptoms [85]. RLS could therefore play a significant pejorative
role on functional outcomes indirectly via impaired quality of
life and depressive symptoms, but also via sleep deprivation
and sympathetic hyperactivity [72].
The specific impact of PLM on post-stroke outcomes has
not been studied.
3.3.4. Specific management of post-stroke RLS or PLM
The beneficial effect of RLS and PLM treatment to improve
neurological recovery and secondary stroke prevention is not
known [12]. However, management of RLS/PLM should
improve quality of life and quality of sleep in those patients
[88]. As in patients free of stroke, and as a prerequisite for an
effective management of RLS/PLM, drug adaptations must be
considered and treatments promoting RLS should be avoided
(i.e. antidepressants [especially mirtazapine], neuroleptics
[except aripiprazole], antiemetics [metoclopramide, metopi-
mazine, droperidol], lithium and hypnotic antihistaminergic
agents). Iron supplementation should be implemented in case
of iron deficiency. Low dose dopamine or alpha 2 delta-ligand
agonist treatments (such as pregabalin or gabapentin), can be
used and are efficient in post-stroke RLS [60]. Finally, if RLS
only occurs intermittently, some specific treatments such as
codeine paracetamol, for example, can be used occasionally,
but it is important to be aware of the associated risk of
inducing central SA.
3.4. Central disorders of hypersomnolence and excessive
daytime sleepiness
Hypersomnia is defined as an excessive need for a certain
amount of sleep over 24 hours, typically more than 9 hours of
sleep during the night and more than 10 hours over 24 hours
[15]. Excessive daytime sleepiness (EDS) is an inability to stay
awake during the normal wake period of the day [15]. These
787
symptoms are different from ‘‘fatigue’’, which is a complaint
of physical and/or mental exhaustion with difficulties in
initiating or sustaining voluntary activities that are not
significantly improved by increased rest or sleep [15].
Screening for EDS is based on self-administered questionnai-
res such as the Epworth sleepiness scale (ESS) [89], and sleep
diary can be used, reflecting sleep/wake habits and EDS over
several weeks [42].
Hypersomnia is more complicated to evaluate: a careful
medical interview, with sleep diary and some actimetric tools
can be used. Objective assessment of hypersomnolence (i.e.
hypersomnia and/or EDS) is made by electrophysiological
testing using multiple sleep latency tests, maintenance of
wakefulness tests or continuous sleep recordings over 24 or
32 hours. In the general population, the prevalence of
hypersomnia varies between 0.3% to 13% and EDS between
8% to 33%; this wide variability in prevalence depends on the
definition or the tool used.
3.4.1. Epidemiology of post-stroke EDS or hypersomnia
Hypersomnia is found in 27% of patients following a stroke,
and EDS in 18% to 72%, with a tendency to improve a few
months after stroke, even if a fatigue complaint persists –
sometimes for years [60]. In a recent prospective study of 473
patients with ischemic stroke, the frequencies of EDS defined
by an ESS > 10 varied between 10–14%, and fatigue was found
in 22–28% of patients. Mean EDS scores decreased two years
after stroke, whereas mean fatigue scores remained stable
[18].
The diagnosis of post-stroke EDS is mainly based on self-
questionnaires such as the ESS, but very rarely on objective
measurements. Post-stroke EDS is associated with RLS,
diabetes, and higher BMI [90]. The localization mostly be
associated with this sleep disorder are subcortical or ponto-
mesencephalic lesions [91]. The most severe hypersomnia is
that associated with thalamic infarctions, and in particular bi-
thalamic stroke (via an occlusion of Percheron’s artery for
example) in which drowsiness can be at the forefront; it
regressed at one year but remained higher compared to the
pre-stroke level [92].
Fatigue and EDS can also be symptoms of SA that should be
suspected when associated with other symptoms such as
snoring, witnessed apneas in a context of obesity or
overweight [43]. Surprisingly, patients with stroke reports
less EDS compared to patients from the general population for
a given level of SA severity [93–95].
3.4.2. Impact of EDS on stroke outcomes
It has been suggested that EDS, hypersomnia and fatigue can
negatively affect stroke recovery, due to their association with
depressive symptoms, greater apathy and by negatively
impacting patients’ participation in rehabilitation after stroke
[22,96]. Only few studies have analyzed the impact of EDS on
post-stroke outcomes. A cohort study of 213 patients showed
that hypersomnia was a risk factor for disability and
institutionalization, however, no adjustment was made for
patients’ medical conditions [97]. Another study on the
evolution of thalamic infarctions showed a higher subjective
total sleep time in patients with poorer recovery [92].
788 revue neurologique 179 (2023) 782–792
3.4.3. Management of post-stroke EDS
An iatrogenic problem must always be evoked, and sedative
treatments (i.e., sedative antidepressants, neuroleptics, or
analgesics) should be avoided or discontinued. Antidepres-
sants with a ‘‘stimulant effect’’ may be used to decrease EDS or
hypersomnia [60,98]. Modafinil, methylphenidate and levodopa
showed a slight benefit on fatigue and quality of life but did not
show any significant benefit on neurological recovery, depres-
sive symptoms and cognitive impairment [99,100]. Moreover,
their effect on EDS or hypersomnia has never been evaluated so
far. In addition, the use of psychostimulant treatments (wake-
promoting agents) can be hazardous in stroke patients, as these
pharmacological agents can promote hypertension and may
worsen cardiovascular risk. Other wake-promoting agents
such as pitolisant [101], acting through histamine, and with
few or no cardiovascular effect could be of interest, but has
never been tested in this population. In patients with SA
managed by CPAP after stroke, a few studies showed an
improvement of EDS [51,102]. However, there is currently no
evidence that treatment of post-stroke EDS or hypersomnia
will improve functional outcomes.
3.5. Circadian rhythm sleep-wake disorders
The circadian rhythm refers to the endogenous clock, which is
responsible for the rhythmicity of a set of biological functions
(such as sleep/wake alternation, hormone secretion, body
temperature, etc.) and their appropriate expression within
24 hours [103,104].
The circadian rhythm disorders include endogenous
alterations such as phase advance or delay syndromes,
irregular sleep/wake rhythm and different than 24-hour
rhythm; and exogenous disorders, such as jet lag or shift
work [103]. The phase delay syndrome is the most common,
affecting 3 to 8% of adolescents and 3% of middle-aged adults.
The advance phase syndrome affects 7.4% of 40–64-year-old
people. Other endogenous circadian rhythm disorders are
extremely rare. Evaluation of the circadian rhythm is based on
sleep diary, actigraphy, or chronotype questionnaires. The
measurement of peak melatonin secretion or internal tempe-
rature over 24 hours can be used, but for research purpose
mainly [103].
No study to date has directly measured the impact of
endogenous circadian rhythm disorders on the risk of stroke.
However, it has been shown that shift work is an independent
risk factor for stroke [105]. Interestingly, stroke occurrence
follows a circadian rhythm with a peak in the morning (between
6 a.m. and noon) [106] and it is estimated that about 20% of
strokes are wake-up strokes [107]. This is probably related to
circadian rhythmicity of the vascular system, with nocturnal
rest (lower blood pressure and heart rate during the night and
morning peak) [108], hormonal changes with a morning peak in
cortisol, a greater blood coagulability in the morning, but also
linked to the REM sleep pressure, this sleep stage being more
frequent in the third part of the night [103,109].
3.5.1. Alteration of circadian rhythm after stroke
Circadian rhythm alterations after stroke have been observed
in several studies. Thus, a reduction in melatonin secretion in
the days following stroke has been described, and is associated
with insomnia, stroke severity and functional outcomes
[110,111]. However, these changes in the melatonin secretion
profile may be of environmental origin rather than being
directly related to stroke, due to changes in light exposure.
Stroke location may however, in some cases, influence
chronotype changes [112]. Other studies have analyzed the
circadian rhythm via actigraphy or chronotype questionnaires
and have shown a more fragmented circadian rhythm in the
early post-stroke phase. These changes were also correlated
with the presence of white matter lesions and microbleeds
[113]. The exact prevalence of post-stroke circadian rhythm
disorders is not known, nor are the potential consequences on
outcomes. Interestingly, melatonin administration in the very
early phase after stroke may have a neuroprotective effect in
animals, with an improvement on functional recovery, but not
on the lesion size. This has not yet been replicated in humans
[114].
4. Perspectives and research agenda
Sleep and stroke are tightly intertwined and post-stroke sleep
is multifaceted, due to the high-frequency of sleep disorders
and the direct impact of stroke itself on sleep duration and
quality. In view of the expected benefits of the treatment of
sleep disorders in secondary prevention (Fig. 1), improved
diagnostic strategies are needed, with the aim of improving
patient management. This could not be achieved without a
multidisciplinary approach, by integrating the transdiscipli-
nary expertise of specialists in stroke, sleep, respiratory and
physical and rehabilitation medicine to optimize sleep health
promotion and the treatment of sleep disorders following
stroke. Due to uncertainties regarding the temporal evolution
of sleep disorders following stroke, there is a need to reassess
sleep quality, duration and disorders at every stroke phase.
Despite major advances in knowledge over the past ten years
on the impact of post-stroke sleep duration, quality and sleep
disorders on stroke outcome, many unresolved questions
remain. The clinical priorities and research perspectives in
this field are the following:
 diagnosis: optimize large-scale screening for sleep disor-
ders, by developing specific questionnaires [42] or by using
simplified diagnostic techniques integrated into routine
post-stroke clinical care. The identification of specific
clinical and imaging biomarkers of sleep disorders following
stroke is mandatory. While research has focused on the
relationships between SA and stroke in the past ten years,
research gaps remain especially regarding insomnia and
RLS/PLMS [12]. Moreover, as most of the studies to date have
been focused on one single sleep disorder, the description of
comorbid sleep disorders associations and their impact on
prognosis are required to improve diagnosis and care,
following the seminal work by Duss et al. [20]. Finally, the
optimal time from stroke to diagnosis and management of
sleep disorders should be further investigated, even if in
most of the cases, the earlier might be the better [12,36];
 management and treatment of sleep disorders: stroke
specific treatment algorithms should be developed and
 revue neurologique 179 (2023) 782–792
validated, taking into account the specificity of the different
post-stroke phases, and the comorbid sleep disorders. In SA,
several studies are ongoing [115];
 risk stratification and biomarkers: for SA, the AHI may not be
the best metric to reflect SA severity [116,117]. Novel metrics,
in particular the hypoxic burden [118,119], arousal fre-
quency, pulse wave amplitude drop [120] and pulse-rate
variability [121] may improve cardiovascular and functional
outcome prediction. Their calculation should be automated
and embedded in future screening tools to be developed;
 sleep and health trajectories: optimizing patient monitoring
approaches, by collecting real-life data on daily activities
using connected devices, could improve the description and
understanding of sleep-related patients’ health trajectories
as well as improving the management of stroke-associated
sleep disorders;
 the effects of hospital conditions, such as adjusting light
conditions according to the patients’ sleep-wake rhythms,
or sleep promoting drugs and non-invasive brain stimula-
tion to promote neuronal plasticity and recovery following
stroke requires further investigation.
Funding
S. Baillieul, J.-L. Pépin and R. Tamisier are supported by ‘‘My
Way to health’’ through the French National Research Agency
in the framework of the ‘‘Investissements d’avenir’’ pro-
gramme (ANR-15-IDEX-02) and the ‘‘e-health and integrated
care and trajectories medicine and MIAI artificial intelligence’’
Chairs of excellence from the Grenoble Alpes University
Foundation. This work has been partially supported by
MIAI@Grenoble Alpes (ANR-19-P3IA-0003).
Disclosure of interest
The authors declare that they have no competing interest.
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