REVIEW ARTICLE
Sleep in Patients With

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
CITE AS:
CONTINUUM (MINNEAP MINN)
2020;26(4, SLEEP NEUROLOGY):
1016–1033.
Address correspondence to
Dr Sara E. Benjamin, Johns
Hopkins Center for Sleep,
11085 Little Patuxent Pkwy,
Ste 210, Columbia, MD 21044,
sbenjam4@jhmi.edu.
RELATIONSHIP DISCLOSURE:
Dr Benjamin has received
personal compensation for a
grand rounds presentation for
Mercy Medical Center; as a
narcolepsy agent formulary
review consultant for OptumRx,
T
Inc; and for occasional surveys
for BioPharm, Compass, Inc,
Everyday Health Group, GLG,
InCrowd, Inc, J Reckner
Associates, Inc, M3 Global
Research, Olson Research
Group, Research Now Group,
LLC, Schlesinger Group, and
WebMD, LLC.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Benjamin reports no
disclosure.
© 2020 American Academy
of Neurology.
1016
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Neurologic Disease
By Sara E. Benjamin, MD
ABSTRACT
PURPOSE OF REVIEW: This
article provides a discussion of the current evidence
and contemporary views on the relationship between sleep disorders and
neurologic disease.
RECENT FINDINGS:Disrupted or disordered sleep can be associated with
increased morbidity and mortality, the risk of cardiovascular events,
increased seizure frequency, and altered immune responses. Studies have
implicated disrupted sleep and circadian rhythm dysfunction with both
amyloid-β (Aβ) deposition and tau deposition. A bidirectional relationship
exists between disrupted sleep and the progression of Alzheimer disease
pathology. Insomnia has been reported as a prodromal symptom in
autoimmune encephalitis. Primary sleep disorders have now been
increasingly recognized as a common comorbid condition in multiple
sclerosis, making it imperative that neurologists feel comfortable
differentiating multiple sclerosis fatigue from excessive daytime
sleepiness caused by primary sleep disorders to optimally treat their
patients.
SUMMARY: Sleep disorders are common across the population. By
recognizing sleep disorders in patients with neurologic conditions,
neurologists can provide comprehensive care and, in some cases, reduce
neurologic disease burden.
INTRODUCTION
he World Health Organization reports that neurologic conditions
contribute to more than 6% of the global burden of disease, with the
impact of disability due to neurologic disease (adjusted in life years)
expected to grow in the next 10 years.1
Sleep disorders are also common across the population. For
example, obstructive sleep apnea (OSA) affects an estimated 26% of the general
population.2 Increasing evidence suggests a strong bidirectional relationship
between the manifestation of sleep disorders and neurologic disease. Disrupted
or disordered sleep can increase the risk of cardiovascular events,3 increase
seizure frequency,2 or alter immune responses.4 At the same time, certain
neurologic disorders place individuals at a higher risk of developing primary
sleep disorders. As outlined elsewhere in this issue, rapid eye movement (REM)
sleep behavior disorder is now strongly associated with future synucleinopathies
and can predate or postdate the more classic symptom manifestation of the
AUGUST 2020
neurodegenerative process. By recognizing and treating sleep disorders, KEY POINTS
neurologists can provide comprehensive care for their patients.
● Obstructive sleep apnea
may lead to inflammation,
STROKE increasing the risk of stroke.
Stroke is one of the most common neurologic conditions treated by neurologists
and a leading cause of death and disability throughout the world. Multiple ● Atrial fibrillation
prevalence is four times
modifiable risk factors for stroke exist, including hypertension, diabetes mellitus,
higher in patients with sleep
hyperlipidemia, smoking status, and physical inactivity.3 Sleep disorders can also apnea, serving as a
contribute to the risk of stroke. significant risk factor for
cardioembolic stroke.
Stroke and Sleep-Disordered Breathing
Sleep apnea is an independent risk factor for stroke.5 Sleep apnea can increase a
patient’s risk of stroke, independent of lesion location.5 In the Brain Attack
Surveillance in Corpus Christi Project cohort, no association was found between
ischemic stroke subtype (large artery atherosclerosis, cardioembolic, small vessel
occlusion, stroke of other determined etiology, or stroke of undetermined
etiology) and the presence or the severity of sleep apnea.6
The prevalence of sleep-disordered breathing in patients who have had a stroke
is much higher than in the general population, and studies cite a prevalence of an
apnea-hypopnea index (AHI) greater than 10 events per hour in 60% of stroke
patients on average compared with 20% of age-matched controls.3 The patients
who have had a stroke who have sleep apnea often have other risk factors such as
male sex, older age, alcohol consumption, cigarette smoking, and atrial fibrillation.3
Despite this increased prevalence, it is uncommon for stroke patients to
receive prompt screening for sleep apnea.7 A population-based study of patients
after stroke as a part of the Brain Attack Surveillance in Corpus Christi Project
found that only 6% of these patients were offered sleep apnea testing within
3 months of their strokes.7 The investigators hypothesize that a lack of physician
awareness of the high prevalence of poststroke sleep apnea or the associated
sequelae of untreated apnea drives this finding. In addition, they note that sleep
apnea is especially underdiagnosed in the general Hispanic population.7
Several mechanisms may contribute to the association between stroke and
sleep apnea. The intermittent hypoxemia associated with sleep apnea may induce
an inflammatory process, leading to endothelial damage, which can lead to
stroke.8,9 Moderate to severe sleep apnea has been correlated with silent ischemic
changes such as white matter changes, lacunar strokes, and cerebral microbleeds.
Sleep apnea may accelerate carotid and intracranial atherosclerosis. It is also
associated with the risk of development of type 2 diabetes mellitus because sleep
apnea can increase insulin resistance and increase cortisol secretion.3
In addition, patients with untreated sleep apnea are at an increased risk of
cardiac embolism. The prevalence of atrial fibrillation is 4 times higher in patients
with sleep apnea. In retrospective trials identifying sleep apnea in patients with
recent stroke, prevalence rates of sleep apnea vary from 50% to 70%.3
Atrial fibrillation rates are highest from midnight to 8:00 AM.3 This overlaps
the circadian window during which individuals are also much more likely to
experience stroke, with the peak stroke incidence just after 8:00 AM.10

Benefits for Treating Sleep Apnea in Patients With Stroke

The SAVE (Sleep Apnea cardioVascular Endpoints) study was an international,
multicenter study designed to determine if treatment of OSA with continuous

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE

FIGURE 10-1
Multiple sleep-disrupting mechanisms may contribute to the development of stroke.
PLMS = periodic limb movements in sleep; RLS = restless legs syndrome.
Reprinted with permission from Koo DL, et al, J Stroke.3 © 2018 Korean Stroke Society.

positive airway pressure (CPAP) therapy along with best medical care compared
with best medical care alone would reduce the risk of serious cardiovascular
events in patients who had established coronary artery disease or cerebrovascular
disease. Portable monitoring devices were used to diagnose sleep apnea.11 The
mean follow-up period for the study was 3.7 years.12 The SAVE trial failed to
demonstrate benefit in using CPAP for cardiovascular end points; however,
mean usage in the CPAP treatment group was only 3.3 hours per night over the
3.7-year trial,12 which was almost 1 hour less use per night than the current
Centers for Medicare & Medicaid Services (CMS) guidelines used to designate
minimal treatment adherence.13
Another consideration in interpreting the methods and results of the SAVE
trial pertains to REM-related apnea specifically. REM-related apnea may have
been incompletely treated because of the short average use time; moreover,
sleep apnea patterns in REM sleep may confer apnea events that are fewer in
number but longer in duration and associated with more severe oxygen
desaturation.3

1018 AUGUST 2020

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 Forty-two percent of the CPAP-treated group had good compliance with KEY POINT
CPAP (more than 4 hours of use per night) during the follow-up period.12 The
● Sleep period length and
patients with good CPAP adherence (mean age, 62.0 years) were slightly older circadian rhythm
compared with the patients with poor adherence (mean age, 60.7 years) and the differences can be linked to
usual care group (mean age, 61.2 years). The baseline AHI was higher in patients ischemic stroke risk.
with good CPAP adherence (mean, 30.2 events per hour) than in the other
groups (mean, 28.2 events per hour for patients with poor adherence and 29.3
events per hour for patients in the usual care group). The mean baseline Epworth
Sleepiness Scale score was only slightly higher in the group with good adherence
(mean score, 7.4) than in the other groups (mean score, 7.2 for the group with
poor compliance and 7.4 in the usual care group).14
Although the primary end points of the study were not reached, secondary
end point benefits to the use of CPAP were noted. The patients who used CPAP
reported reduced snoring and daytime sleepiness as well as improvements in
mood and quality-of-life ratings. This included reductions in anxiety and
depression scale scores and fewer days missed from work due to poor health.12
The SAVE trial excluded very sleepy patients who had a baseline Epworth
Sleepiness Scale score greater than 15.14 Patients with severe hypoxemia or
Cheyne-Stokes respiration were also excluded.12 More studies are needed to
understand the risk factor reduction benefit of OSA therapy with specific
populations and to understand the long-term benefit in consistent (more than
4 hours per night) CPAP use. In addition, more trials are needed to assess the
cardiovascular benefits of alternative treatments of sleep apnea, such as
hypoglossal nerve stimulation and oral appliance therapies.
Other sleep disruptions may also contribute to stroke (FIGURE 10-1). Both
short and long sleep durations have been associated with higher rates of stroke.3
A long sleep duration may indicate comorbid medical conditions with a higher
risk of mortality and cardiovascular events. Patients who have short sleep
durations may have sleep deprivation that can lead to increased ghrelin and
reduced leptin secretions, factors that may lead to the development of obesity.
Short sleep duration may also lead to sympathetic overactivity and, therefore, to
impairment of glucose metabolism, altering the metabolism of lipids and leading
to hypertension.3
Patients who have circadian rhythm shift work disorder or professions
associated with prominent shift work schedules have higher rates of
cardiovascular events. A large cohort study of nurses found that, after adjusting for
other risk factors, working a rotating night shift was associated with a 4% increased
risk of ischemic stroke for every 5 years of adhering to that schedule type.3 Periodic
limb movements with arousals have been linked to cardiovascular events, likely
associated with blood pressure spikes associated with the leg movements.3
The American Heart Association recommends initiating screening for sleep
apnea by taking a careful history and asking about apnea witnessed by a sleep
partner, episodes of choking or gasping during sleep, insomnia with repeated
awakenings, excessive daytime sleepiness, or nonrestorative sleep. Other
symptoms to consider include morning headaches, difficulties with memory or
concentration, irritability or mood changes, nocturia, or sexual dysfunction.
More recently, single questions asked of a bed partner about the “positive elbow
sign,” which inquire about the frequency of receiving an “elbowing” from a bed
partner to roll over due to loud snoring or observed stopping breathing, have also
found promise for their predictive value for clinically significant sleep apnea.15

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE
KEY POINTS
● Sleep apnea can be both
screened for and diagnosed
with various valid tools that
include questionnaires that
can be completed by the
patient or care provider and
with in-center or ambulatory
sleep diagnostic services.
● When deep sleep is
attenuated, amyloid-β (Aβ)
and tau protein, which are
hallmarks for Alzheimer
disease, can accumulate.
● Patients with Alzheimer
disease often have an
irregular sleep-wake
rhythm. Behavioral
interventions, including
appropriate timing of
natural-light exposure and
physical activity, may be
helpful in reinforcing an
appropriate circadian
rhythm.
● Rapid eye movement
(REM) sleep behavior
disorder is commonly
a precursor to
α-synucleinopathies with
reported presentation as
much as 10 to 15 years prior
to Parkinson disease motor
manifestations.
1020
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Ideally, a practitioner should use standardized questionnaires, such as the STOP-
BANG questionnaire, the Epworth Sleepiness Scale score, or the Berlin Questionnaire.
Next, a physical examination should be performed with attention to the airway and
cardiovascular system as well as a review of the patient’s history for relevant
comorbidities. If these factors point to underlying sleep apnea, an attended laboratory
polysomnogram or a home sleep test should be performed for evaluation.16 For
further information about obstructive sleep apnea, refer to the article, “Obstructive
Sleep Apnea,” by Douglas B. Kirsch, MD, FAAN,17 in this issue of Continuum.
ALZHEIMER DISEASE/COGNITION
Both amyloid-β (Aβ) and tau protein are pathologic hallmarks of Alzheimer
disease. The deposition of these proteins can occur more than a decade before the
onset of symptoms of Alzheimer dementia. Studies have implicated disrupted
sleep and circadian rhythm dysfunction in both Aβ deposition and tau
deposition. The relationship between disrupted sleep and the progression of
Alzheimer disease pathology is bidirectional (FIGURE 10-218).
Mechanistic links have been identified between the glymphatic clearance of
Aβ and the sleep-wake rhythm. Moreover, changes in CSF Aβ levels and
increases in Aβ burden in the thalamus and hippocampus have been seen after
one night of disrupted sleep in healthy middle-aged adults, suggesting that
chronic sleep deprivation may promote Aβ plaque accumulation by reduced
glymphatic clearance.19 In addition, other studies have demonstrated that CSF
tau levels are also raised after just one night of sleep deprivation, and in an animal
model, tauopathy increases with sleep deprivation.19 Although circadian sleep
phase advancement is commonly seen with normal aging, patients with
Alzheimer disease often have an irregular sleep-wake rhythm, clinically
manifesting in symptoms typically described as “sundowning.”20 Sundowning is
FIGURE 10-2
Sleep deprivation promotes Alzheimer disease pathology. During sleep, increased
clearance of amyloid-β (Aβ) and tau from the brain occurs. Sleep deprivation reduces this
clearance and promotes astrogliosis, network activity-driven tau and Aβ release, further
protein aggregation, and the spread of Alzheimer disease pathology.
Reprinted with permission from Noble W, Spires-Jones TL, Science.18 © 2020 American Association for
the Advancement of Science.
AUGUST 2020
a common phenomenon in Alzheimer disease and is observed in about 25% of
patients with Alzheimer disease.20 The neuroanatomic correlates to this
phenomenon include postmortem neuropathologic studies of patients with
Alzheimer disease that have demonstrated a critical loss of neuronal populations
in the suprachiasmatic nucleus, including cells that express arginine vasopressin
or vasoactive intestinal peptide.20
Studies using actigraphy demonstrate that physical activity can be spread
across a 24-hour day.20 A correlation exists between regular nocturnal motor
activity and aggressive behavior and agitation. Strategies to mitigate this focus on
optimizing medications, managing medical and psychiatric comorbidities, and
improving sleep hygiene. Many patients with Alzheimer disease have very little
bright natural-light exposure during the day. More exposure to natural bright
light during the day may reduce sundowning behavior.21 In addition, melatonin
may benefit patients with Alzheimer disease by multiple mechanisms, including
regulation of the circadian rhythm and, thereby, alleviating sundowning and its
role as a free radical scavenger.22 Sundowning may be associated with the
hypersecretion of cortisol in patients with Alzheimer disease due to
hypothalamic-pituitary-adrenal axis dysfunction. A regular afternoon exercise
program (specifically, in a trial by Venturelli and colleagues,23 1 hour of walking
with a caregiver) has been demonstrated to reduce cortisol levels and
simultaneously reduce sundowning behaviors.

PARKINSON DISEASE
Parkinson disease does not confer a higher risk of OSA; however, other impacts
of Parkinson disease and related disorders on sleep exist. Sleep-related symptoms
collectively represent one of the most common (nonmotor) and often
debilitating concerns reported in patients who have Parkinson disease
(TABLE 10-124). The most notable association is the link between REM sleep
behavior disorder (RBD) and Parkinson disease.
RBD is considered a precursor to α-synucleinopathies, such as Parkinson
disease and dementia with Lewy bodies. This symptom can present 10 to 15 years

Factors That Increase the Risk of Conversion From Idiopathic Rapid Eye TABLE 10-1
Movement Sleep Behavior Disorder to Parkinson Diseasea

◆ Family history of Parkinson disease

◆ Older age
◆ Nonuse of antidepressants
◆ Subtle motor or cognitive dysfunction
◆ Orthostatic hypotension
◆ Constipation
◆ Hyposmia
◆ Early imaging findings (positron emission tomography [PET]–single-photon emission
computed tomography [SPECT] scan)

a
Data from Barber TR, et al, Sleep.24

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE

before motor symptoms of Parkinson disease.25 Rates of the eventual

development of neurodegenerative disease are greater than 80%.24 RBD and
hyposmia are the two features of the prodromal patients who are being followed
as a part of the Parkinson’s Progression Markers Initiative, an observational,
longitudinal study that is currently underway to confirm the prodromal markers
of Parkinson disease.26 Patients with RBD may also be at higher risk of cognitive
decline associated with Parkinson disease.25
Patients who present with RBD have frequent comorbidities, including
depression and sleep apnea. The use of antidepressant medications can unmask
RBD at an earlier age (therefore, patients on antidepressant medications who
have RBD may have lower rates of conversion to Parkinson disease as they have
more years of RBD only without parkinsonian symptoms). Respiratory
disorders, like sleep apnea, can have a similar effect. Thirty-four percent to 61%
of patients with RBD may have sleep apnea.21
Epidemiologic studies have looked for an association between restless legs
syndrome (RLS) and other movement disorders. Some of the groups report a
higher than expected prevalence of RLS in patients with Parkinson disease.27 The
mechanism underlying the increased prevalence remains somewhat controversial
with implications ranging from an extension of the neurodegenerative disease
process of Parkinson disease compared with a more drug-induced etiology due to
the use of dopamine agonists or dopamine-containing drugs as treatments. In
particular, higher rates of RLS are reported in treated patients27 and in patients
with advanced Parkinson disease, making one consider if a phenomenon such as
augmentation from dopamine agonists and dopamine agents is conferring RLS.
For patients already diagnosed with Parkinson disease, sleep disruption is
frequently a part of the disease course. As many as 80% of patients with

TABLE 10-2 Frequency of Selected Nonmotor Symptoms (Nonsleep- and

Sleep-Related) in Patients with Parkinson Disease and in Controlsa

Patients with
Symptom Parkinson Disease (%) Controls (%) P Value

Sialorrhea 56 6 <.001

Constipation 42 7 <.001

Urinary urgency 47 19 <.001

Hyposmia 45 10 <.001

Daytime somnolence 37 18.2 .001

Insomnia 18 13 .385

Dream reenactment 35 8 <.001

Vivid dream imagery 30 5 <.001

Restless legs 38 3 .002

Unexplained pain 38 3 <.001

a
Modified with permission from Khoo TK, et al, Neurology.28 © 2013 American Academy of Neurology.

1022 AUGUST 2020

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Parkinson disease experience this type of disturbance, making it the major KEY POINTS
nonmotor clinical symptom (TABLE 10-228).20 Excessive daytime sleepiness is a
● Sleep disruption is
common complaint in patients with Parkinson disease, who often report common in Parkinson
sleepiness at twice the rate of their age-matched counterparts without Parkinson disease, and this often leads
disease, particularly after the age of 60 years. The change in circadian rhythm to excessive daytime
associated with Parkinson disease is characterized by a diminution in the sleepiness in this patient
population.
magnitude of the circadian rhythm without a strong circadian phase shift.20
In addition, some studies have reported that treatment with dopamine ● Huntington disease and
agonists may be associated with circadian rhythm dyssynchrony, potentially due palatal myoclonus represent
to disruption in melatonin secretion and, thereby, uncoupling circadian and the two movement
sleep-wake regulation.20 disorders for which
movements have been
Patients with dementia with Lewy bodies have frequent arousals from sleep commonly recognized to
that cannot be explained by sleep-disordered breathing or by movements. A persist while sleeping,
primary sleep disorder has not been specifically implicated in the poor sleep unlike other movement
efficiency that is often seen in these patients, thereby suggesting that the sleep disorders such as Parkinson
disease, where sleep allows
disruption may be inherent to the neurodegenerative process itself.29 for a quiescent phase in the
stereotyped movements.
HUNTINGTON DISEASE
Patients with Huntington disease may have circadian dysfunction (both
advanced sleep phase and delayed sleep phase have been reported) that can be
associated with increased anxiety and depression and decreased cognitive
performance.30,31 Often, sleep disturbances are one of the earliest
presentations of the disease. Past studies found that the degree of sleep
disturbance does not correlate with the length of the CAG repeat, but some
studies have revealed that CAG repeat length is associated with a reduction of
slow-wave sleep.32,33 A disturbance in sleep maintenance is a prominent
symptom, and awakenings can be associated with EEG abnormalities.
Awakenings may also be associated with anxiety and choreiform
movements.31 The disturbances can include nightmares, feeling hot or cold,
coughing, or snoring.31 Decreased N3 sleep and increased spindle density may
be observed.
Huntington disease and palatal myoclonus represent the two movement
disorders for which movements have been commonly recognized to persist while
sleeping, unlike other movement disorders such as Parkinson disease whereby
sleep allows for a quiescent phase in the stereotyped movements.34
Later in the disease course of Huntington disease, patients may develop
rigidity and bradykinesia, which make it difficult to change sleep position and
thereby interfere with the ability to sleep.31 RLS and periodic limb movements of
sleep can also impact patients with Huntington disease.31

SLEEP AND IMMUNE-MEDIATED NEUROLOGIC DISEASES

It may be commonly considered that a person needs more sleep when fighting an
infection or an autoimmune disease, yet sleep disruption and insomnia are key
features of some immune-related disease states.

General Considerations
Mechanistic investigations to further understand the association between
immunologic function and regulation and sleep have grown exponentially in the
past 10 to 15 years.4 Non-REM sleep seems to be the sleep phase with the greatest
immune system interrelationship. Thermoregulation is strongest during this

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE

sleep phase. In the setting of infections, sleep regulatory substances such as

interleukin-1, interleukin-6, and tumor necrosis factor–α are increased, which
leads to a longer duration of sleep and an increased proportion of non-REM
sleep to REM sleep. Therefore, in the setting of sleep deprivation, the immune
system is less capable of mounting a robust immune response, and this blunted
response has even been implicated in the possible variability seen in vaccine
response and effectiveness.4

Autoimmune Encephalitis
Forms of autoimmune encephalitis are receiving increased recognition with
more autoantibodies described every year. About one-third of all encephalopathy
cases are now thought to be immune mediated, and these cases require a high
level of health care resources.35 Autoimmune encephalitis as a group is strongly
associated with subacute cognitive changes, encephalopathy, and seizures.
Reports of associated sleep disturbances and disorders are increasing
(TABLE 10-336).
Insomnia has been reported as a prodromal symptom in autoimmune
encephalitis.37 A 2019 study looked at the prevalence and subtype of sleep
disorders in a cohort of patients with autoimmune encephalitis at an academic
medical center.36 Seventy-three percent of the patients had a new or worsened
sleep disturbance, including sleep apnea and RBD. Specifically, RBD was
associated with leucine-rich glioma inactivated 1 (LGI1) autoantibodies and
N-methyl-D-aspartate (NMDA) receptor autoantibodies. In addition, sleep
architecture was disrupted in these patients, with prominent sleep fragmentation
and an abundance of N1 and N2 sleep and a loss of N3 and REM sleep.
Other findings include periodic limb movements of sleep and RLS symptoms,
as well as insomnia. Treatable disorders such as sleep apnea and RLS should be
addressed in these patients to improve their quality of life.36
For patients with immunoglobulinlike cell adhesion molecule 5 (IgLON5)
disease, disrupted sleep is the predominant concern. The disease is characterized
by serum and CSF autoantibodies against the neuronal surface protein IgLON5.38
The most common sleep features of this disease are complex sleep behaviors in
non-REM sleep, RBD, and OSA with stridor. Neurologic abnormalities may
include bulbar symptoms and gait abnormalities.38 In a case report study of a

TABLE 10-3 Some Associations Between Autoantibodies and Sleep Disordersa

Autoantibody Sleep Disorders Commonly Observed

LGI1, CASPR2 Rapid eye movement (REM) sleep behavior disorder

Ma autoantibodies Hypersomnia, fragmented sleep

DPPX autoantibodies Insomnia, periodic limb movements

IgLON5 autoantibodies Sleep-disordered breathing

CASPR2 = contactin-associated proteinlike 2; DPPX = dipeptidyl-peptidase–like protein 6; IgLON5 =

immunoglobulinlike cell adhesion molecule 5; LGI1 = leucine-rich glioma inactivated 1.
a
Data from Blattner M, et al, J Neurol.36

1024 AUGUST 2020

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patient with anti-IgLON5 encephalopathy, 1 year of immunotherapy with KEY POINTS
monthly IV immunoglobulin (IVIg), prednisone, and azathioprine led to the
● Insomnia and other sleep
progressive improvement of gait ataxia, cognitive function, and both daytime disturbances are often
sleepiness and motor activation during sleep.39 A home unattended sleep study prodromal symptoms in
demonstrated improvements in sleep architecture.39 Future directions for this autoimmune encephalitis.
severe disease process include standardizing a treatment regimen.
● Anti-IgLON5 disease
is an autoimmune
Multiple Sclerosis encephalopathy with sleep
Patients with multiple sclerosis (MS) often report insomnia. This can be disruptions as a prominent
associated with anxiety and depression as well as with pain. part of the presentation.
Patients with MS who have disrupted sleep have higher rates of cognitive Other common features are
bulbar symptoms and gait
dysfunction.40 Perhaps the most prevalent complaint in patients with MS, disturbance.
reported by 80% to 90%, is excessive daytime sleepiness/fatigue.4 When
evaluating a patient with MS, it is important to decipher between fatigue (feeling ● Fatigue and excessive
run down) and excessive daytime sleepiness (at risk of falling asleep), which may daytime sleepiness are
common symptoms
point to a primary sleep disorder. experienced by patients
The National Multiple Sclerosis Society describes MS-related fatigue, different with multiple sclerosis.
from other fatigue, with the following characteristics41: Optimizing approaches to
help distinguish symptoms
of fatigue from sleepiness
u Generally occurs on a daily basis can improve early
u May occur early in the morning, even after a restful night’s sleep identification of underlying
sleep disorders and,
u Tends to worsen as the day progresses therefore, overall
u Tends to be aggravated by heat and humidity management of these two
common and debilitating
u Comes on easily and suddenly functional symptoms.
u Is generally more severe than normal fatigue
u Is more likely to interfere with daily responsibilities

MS-related fatigue does not appear to be directly correlated with either

depression or the degree of physical impairment. It is often the most prominent
symptom in a patient who otherwise has minimal limitations in activity/physical
function.
The cause of both fatigue and excessive daytime sleepiness in patients with MS
is most likely multifactorial including one or a combination of the following
factors: (1) sleep disturbance, including due to primary sleep disorders such as
insomnia, RLS, or sleep apnea; (2) iatrogenic factors such as the use of sedating
medications; (3) highly concentrated proinflammatory cells or sleep regulatory
substances; (4) demyelination of the sleep-wake pathway; (5) dysregulation of
the hypothalamic-pituitary axis; and (6) psychiatric comorbidities that can be
associated with fatigue and sleepiness.6
The manifestations of specific sleep disorders and sleep concerns for patients
with MS have also been linked to the location and the burden of disease.42
Insomnia presenting in the context of nocturia suggests a possible lesion burden
in the micturition center in the pons or lesions in the sacral spinal cord. MS
lesions that affect the medullary respiratory center have been more strongly
associated with central sleep apnea. RLS is also more prevalent in patients with
MS, with prevalence estimates of 3 to 5 times the rate seen in the general
population.4,42 Patients with spinal cord lesions may be at risk of RLS, especially
with spinal lesions involving the descending dopaminergic fibers that can affect

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE

both sensory and motor function.42 Other risk factors for RLS include longer MS
disease duration, older age, primary progressive forms of the disease, and
increased leg movement before sleep onset.4
Increasing evidence suggests a strong association clinically and
mechanistically between MS and narcolepsy. Some patients with both conditions
have hypothalamic lesions that correlate with the symptoms of narcolepsy, and
other patients have both disorders without imaging correlating with the
narcolepsy symptoms. CASE 10-1 presents a patient with narcolepsy without
cataplexy and no hypothalamic demyelination on MRI.
Evidence has been mounting that narcolepsy, and particularly narcolepsy with
cataplexy, is an immune-mediated disorder; a selective loss of orexin
(hypocretin) cells occurs in the posterior hypothalamus. Patients who have
narcolepsy with cataplexy have low orexin (hypocretin) levels. Narcolepsy is
associated with human leukocyte antigen (HLA)-DQB1*06:02, polymorphisms
in the T-cell receptors, and other immune alterations. Cases of narcolepsy have
been triggered by infections, particularly streptococcus and H1N1 virus.43
Similarly, MS is thought to be related to immune dysfunction, without a
known antigen specificity.
In addition, cases of patients with neuromyelitis optica antibodies with
hypothalamic lesions and associated narcolepsy have been reported. Similar to
the patients who have MS with these lesions, these patients have excessive
daytime sleepiness without cataplexy.44

NEUROMUSCULAR DISEASES
Neuromuscular diseases may affect the peripheral nerve, muscles, or the
neuromuscular junction. Many neuromuscular diseases also have systemic
involvement with other associated features. Perhaps the most well-known
concern regarding sleep in these patients is neuromuscular weakness of
respiratory muscles, but other factors can cause sleep disruption.

Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus,
affecting 20% to 60% of patients with type 2 diabetes mellitus. OSA has an
increased predominance in patients who are diabetic; at the same time, those
with diabetic peripheral neuropathy have even higher rates of sleep disturbances.
A 2018 study looked at polysomnography and multiple sleep latency test findings
in 30 patients who were diabetic and compared the group with neuropathy to
the group without this complication. The patients with neuropathy had higher
rates of OSA, and this was often accompanied by signs of dysautonomia, such as
postural systolic hypotension and postural orthostatic tachycardia. In addition,
these patients had more sleep fragmentation, reduced sleep efficiency, and
periodic limb movements of sleep. This disturbed sleep can lead to daytime
symptoms such as excessive daytime sleepiness and impairments in mood and
cognition.45

Myotonic Dystrophy
Patients with myotonic dystrophy commonly report excessive daytime
sleepiness and nonrestorative sleep. About one-third of patients with myotonic
dystrophy have hypersomnolence, which correlates with the degree of motor
impairment from the disorder. The prevalence of nocturnal hypoxemia is high in

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the setting of both obstructive and central sleep apnea in patients with myotonic KEY POINTS
dystrophy who have excessive daytime sleepiness. These patients also have
● If a patient with multiple
nocturnal hypoventilation due to respiratory weakness. In a 2019 study, central sclerosis reports severe
sleep apnea was seen in 25% of the patients with myotonic dystrophy type 1.46 daytime sleepiness that
The authors of that study hypothesized that central respiratory instability leads does not correlate with the
to transient hyperventilation overcompensating mild hypercapnia during sleep onset of other multiple
sclerosis symptoms, an
in patients who have respiratory weakness. Overnight transcutaneous
evaluation for a coexisting
capnography is the recommended method to detect nocturnal hypoventilation in sleep disorder, such as
these patients.46 obstructive sleep apnea
(using polysomnography)
and particularly narcolepsy
Epilepsy
(using polysomnography and
OSA is prevalent in patients with epilepsy, with rates from 30% to 49% in multiple sleep latency
observational studies. The highest prevalence has been found in studies that testing), should be
looked at video-EEG monitoring and epilepsy surgery candidates compared with considered.
patients recruited in the outpatient setting. The risk factors for OSA are similar to
● Risk factors for sleep
those in the general population including obesity, male sex, and history of apnea in patients with
hypertension.47 In a study of patients in an epilepsy monitoring unit, more than epilepsy include seizure
60% of the patients met the criteria for sleep apnea, mostly obstructive in medications that cause
nature.48 Interestingly, many patients with psychogenic, nonepileptic seizures weight gain, benzodiazepine
medication use, and
also have sleep apnea, which may relate to the higher than average BMI reported obstructive and central
in this cohort compared with the general population. sleep apnea events
Some antiepileptic drugs are associated with weight gain, which could associated with a vagal
exacerbate OSA. Benzodiazepines may reduce the tone of the upper airway nerve stimulator.
muscles and blunt the ventilatory response to hypoxia.47
Untreated sleep apnea may alter sleep architecture, increasing N2 sleep and
decreasing N3 and REM sleep. These changes in sleep architecture may
exacerbate cortical excitability in patients with epilepsy and may, thereby,
increase the risk of seizures. Associations have been made between oxygen
saturation levels during REM sleep and cognitive domains that include attention
and executive function in individuals with epilepsy.49
Vagal nerve stimulation (VNS) was approved by the US Food and Drug
Administration (FDA) in 1997 as an add-on therapy for partial seizures that are
incompletely controlled by antiepileptic medications.50 VNS has been
demonstrated to cause both obstructive and central breathing events in several
studies. Marzec and colleagues51 performed polysomnography on 16 patients
with medically refractory epilepsy before placement of the VNS device. At
baseline, 1 of the 16 patients had an AHI greater than 5 events per hour. After the
VNS insertion, 5 of the 16 patients had an AHI greater than 5, with the majority of
the breathing events corresponding to VNS activation (on time). One of those
patients had a history of witnessed apnea and snoring. Another had a previous
tonsillectomy to treat sleep apnea. One of the patients with apnea had more rapid
cycling (a faster time for the stimulation to change from on to off) than others in
this study. This was followed by esophageal pressure monitoring in seven
patients, which demonstrated an increase in esophageal pressure during VNS
activation.51 Marlow and colleagues52 studied four patients before VNS
placement and then again 3 months later. They noted that all the patients had a
reduction in airflow and effort in sleep during VNS activation, but not all events
met the criteria for apnea and hypopnea.
A VNS manufacturer has outlined this in their safety guidelines and noted that
rapid cycling can increase the number of respiratory effort–related arousals per

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE

CASE 10-1 A 40-year-old woman presented to the sleep clinic because of excessive
daytime sleepiness. She had a history of secondary progressive multiple
sclerosis (MS) and a long history of excessive daytime sleepiness which
she believed started 1 year after menarche. Her sleepiness was so severe
that she would pause midconversation to take a 10-minute nap. She was
diagnosed with MS at age 34 but said that she had symptoms of MS since
age 20. She developed bilateral numbness and tingling up to the
fingertips around that age, and at that time, MRI showed a lesion in the
spinal cord, but a brain MRI was normal. Three years later, she developed
left optic neuritis, and MRI of the brain was reportedly normal. At age 34,
she developed left-sided tingling, numbness, and weakness while she
was pregnant, and her MRI showed lesions in the spinal cord and brain,
leading to a formal diagnosis of MS. Serum neuromyelitis optica antibody
was negative.
She recalled “easily” falling asleep in high school, and she
remembered college friends joking that she had narcolepsy. At her first
job, she would take brief naps in the stall during her bathroom breaks. At
the time of presentation, she reported poor nighttime sleep and
excessive daytime sleepiness. She held a full-time job but went back to
sleep after getting her child on the school bus and had a later than usual
start time for her work. She denied cataplexy, hypnagogic hallucinations,
and sleep paralysis. Her only medication was rituximab infusions. Her
Epworth Sleepiness Scale score was 15 (FIGURE 10-3).
At presentation in the sleep clinic, her physical examination was
significant for a BMI of 36 kg/m2, a modified Mallampati classification of
IV (her soft palate was not visible at all when she sat up, opened her
mouth, and extended her tongue), left leg weakness, and spasticity with
3+ reflexes throughout.
After a home sleep apnea test did not demonstrate sleep apnea, she
came to the sleep laboratory for polysomnography followed by a
multiple sleep latency test.
She had a mean sleep latency of 1.4 minutes across the five naps with
sleep-onset rapid eye movement (REM) revealed on all five nap trials.
Between the nap periods, the sleep technician noted that the patient was
awake, pleasant, and conversational with the sleep center staff and even
made phone calls to her family.
MRI of the brain 1 month after her polysomnography and multiple sleep
latency studies demonstrated a stable-appearing T2 hyperintensity along
the undersurface of the corpus callosum with few periventricular white
matter lesions of the bilateral corona radiata with minimal loss of volume
of the posterior body of the corpus callosum. No evidence of new lesions
was seen. These findings were stable over at least 5 years. No
hypothalamic brain lesions were present. Past studies demonstrated a
spinal cord lesion predominant form of MS.

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FIGURE 10-3
Epworth Sleepiness Scale score for the patient in CASE 10-1.

This patient’s presentation is most consistent with two neuroimmunologic COMMENT

conditions: narcolepsy type 2 (narcolepsy without cataplexy) and secondary
progressive MS. This case underscores the importance of clinically
distinguishing MS-related fatigue from new-onset, insatiable, excessive
daytime sleepiness representing a particularly common phenomenology of
narcolepsy. Due to the comorbid presentation of MS, her symptoms had
been attributed mistakenly to MS, potentially contributing to the 20-year
delay between her narcolepsy symptom manifestation and eventual workup
and diagnosis.

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SLEEP IN PATIENTS WITH NEUROLOGIC DISEASE

hour of sleep and reducing the pulse width, stimulation frequency, or output
current may help improve the sleep apnea.47
Some retrospective studies have demonstrated that CPAP use can improve
seizure control, but a randomized double-blind pilot study that randomly
assigned 35 patients who had an AHI greater than 5 but less than 50 to CPAP or
sham CPAP for 10 weeks failed to demonstrate the effect of CPAP on seizure
control in drug-resistant epilepsy.53 New trials have been planned to further
investigate the potential benefit of OSA treatment in the management of
epilepsy in patients with both conditions.47 Treating sleep apnea in these
patients may be challenging; a study of CPAP adherence in patients with
epilepsy versus controls demonstrated that patients with epilepsy are less likely
to adhere to therapy in the first month of treatment.2 Treatment adherence at
3 months and 1 year was also lower than in the patients who did not have
epilepsy, but this represented a trend not meeting statistical significance. In
addition, using CPAP did not normalize the AHI in more than 70% of the
epilepsy patients who were studied.2
An unfortunate additional challenge in the field of epilepsy is to prevent
sudden unexpected death in epilepsy (SUDEP). A multicenter epilepsy
monitoring study looked at respiratory parameters before and after seizure
events. They identified ictal central apnea in patients with focal epilepsy and
postconvulsive central sleep apnea in patients with focal epilepsy and patients
with generalized epilepsy. The postconvulsive central apnea was observed in two
patients with near SUDEP and one probable case of SUDEP, leading to the
conclusion that these respiratory phenomena may be a clinical biomarker for
SUDEP.54

HEADACHES
The most common sleep symptom of patients with both chronic tension
headaches and chronic migraine headaches is insomnia.55,56 Sleep disturbances,
particularly insomnia, can trigger headaches. Other associations include a
significantly higher prevalence of RLS in patients who have tension headache
compared with the general population and more frequent tension headaches in
patients who have shift work disorder.56 Looking at the influence of chronotype
on migraine characteristics, researchers found decreased headache frequency in
early-rising patients compared with late-rising patients; however, headache
severity did not differ.57
Studies have demonstrated overall headache and sleep symptom
improvements for patients who concurrently have both insomnia and
tension/migraine headache who underwent cognitive-behavioral therapy for
insomnia.55,56
Cluster headaches are associated with a nocturnal predilection, but an
actigraphy study failed to find a difference in the sleep patterns of patients who
have cluster headache who are actively having cluster headaches compared with
their sleep patterns during remission.58
A rarer headache type (0.07% to 0.1% of diagnosed headache types) that is
strongly associated with sleep is hypnic headache. Hypnic headaches are defined
by a dull pain that starts during sleep and awakens the patient. The pain occurs 10
or more days per month, and the pain lasts longer than 15 minutes. These
headaches can occur in any age group but are most common in older adults.
Patients with this condition are found worldwide with a nonhereditary

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transmission. First-line headache prophylactic treatments include lithium, KEY POINTS
caffeine, indomethacin, and melatonin.59
● Further studies are
needed to better classify
the impact on seizure
CONCLUSION control incurred by treating
A bidirectional relationship exists between impaired sleep and a variety of sleep apnea.
neurologic conditions. Of particular note, research has looked at the attenuation
● Central sleep apnea and
of deep sleep in the setting of Alzheimer disease pathology, RBD as a precursor of sudden unexpected death in
synucleinopathies, and insomnia and other sleep disturbances as prodromal epilepsy (SUDEP) may be
symptoms in autoimmune encephalitis. Sleep apnea is a risk factor for stroke, related.
and screening patients who have stroke for sleep apnea is an important part of
● Both migraine headaches
secondary stroke prevention. Patients who have MS often report fatigue, but this and tension headaches are
fatigue needs to be distinguished from excessive daytime sleepiness associated exacerbated by poor sleep.
with a sleep disorder.
To offer comprehensive care to neurologic patients, it is important to ask ● Patients who
concurrently have
questions about sleep. Neurologists must consider if a primary sleep disorder,
migraine/tension headaches
such as sleep apnea, insomnia, or RLS, may be affecting the patient. Taking a along with insomnia have
careful sleep history also helps neurologists better understand the patient’s reported dual symptom
lifestyle and helps cater care on an individual basis. When appropriate, sleep benefit after undergoing
cognitive-behavioral
testing or a referral to a sleep medicine provider should be considered.
therapy for insomnia.

● Hypnic headaches are a

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