Accepted Manuscript

Title: Autonomic dysfunction in primary sleep disorders

Author: Mitchell G. Miglis

PII: S1389-9457(15)02010-9
DOI: http://dx.doi.org/doi: 10.1016/j.sleep.2015.10.001
Reference: SLEEP 2917

To appear in: Sleep Medicine

Received date: 6-7-2015

Revised date: 8-9-2015
Accepted date: 12-10-2015

Please cite this article as: Mitchell G. Miglis, Autonomic dysfunction in primary sleep disorders,
Sleep Medicine (2015), http://dx.doi.org/doi: 10.1016/j.sleep.2015.10.001.

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 Autonomic Dysfunction in Primary Sleep Disorders

Mitchell G. Miglis, MD

Highlights:

 Cell populations that help regulate the sleep and waking state are

closely situated to cell populations that help regulate autonomic

function.

 Non-REM sleep is a state of relative autonomic stability and

metabolic recovery, while REM sleep is a state of autonomic

instability.

 Obstructive sleep apnea can result in a major stress on the autonomic

nervous system and lead to significant morbidity and mortality.

 Sleep deprivation alone can increase sympathetic drive.

 Autonomic complaints are common in patients with restless leg

syndrome.

 There is a close association between REM behavior disorder, alpha

synucleinopathies, and autonomic dysfunction.

Page 1 of 63
Abstract: The autonomic nervous system plays an important role in the

coordination of many important physiologic functions during sleep. Many

patients with untreated sleep disorders will describe symptoms of autonomic

impairment, and a majority of patients with autonomic impairment have

some form of sleep disorder. This article will explore possible explanations

for this connection, as well as review the current literature on autonomic

impairment in common primary sleep disorders including obstructive sleep

apnea, insomnia, restless legs syndrome, periodic limb movement disorder,

narcolepsy and rapid eye movement sleep behavior disorder.

Keywords: Sleep; autonomic; sleepiness; obstructive sleep apnea; insomnia;

restless legs syndrome; periodic limb movement disorder; narcolepsy; rapid

eye movement behavior disorder.

Abbreviations: Autonomic nervous system (ANS), Rapid eye movement

(REM), Rapid eye movement sleep behavior disorder (RBD), Obstructive

sleep apnea (OSA), Periodic limb movements (PLMs), Restless legs

syndrome (RLS), Parkinson’s disease (PD), Norepinephrine (NE),

Acetylcholine (ACH), Fatal familial insomnia (FFI)

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Disclosures: Dr. Miglis has nothing to disclose

Corresponding author: mmiglis@stanford.edu

Address:

Department of Neurology

Stanford University

211 Quarry Rd, 2nd Floor

M/C 5992

Stanford, CA94305

Introduction

The autonomic nervous system (ANS) plays an important role in the

coordination of many bodily functions during sleep. It is not uncommon for

patients with untreated sleep disorders to describe symptoms of autonomic

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impairment, and a majority of patients with autonomic impairment have

some form of sleep disorder. This article will explore possible explanations

for this connection, as well as review the current literature on autonomic

impairment in several common primary sleep disorders. While sleep

disorders are common in patients with autonomic disorders, this article will

focus primarily on the autonomic impairment seen in disorders of patients

most frequently encountered in the sleep clinic.

1. Neuroanatomy of the ANS and the Sleep/Wake System

In order to understand the link between sleep disturbances and

autonomic dysfunction, it is important to examine the neuroanatomy of the

ANS and the sleep/wake system. The autonomic cell populations in the

hypothalamus and upper brainstem lie in close proximity to cell populations

integral to the regulation of sleep and arousal. For many years it was thought

that sleep was regulated by the reticular activating system, however it is now

understood that sleep is promoted by neurons in the ventrolateral preoptic

nucleus of the thalamus (Saper, 2002). These neurons secrete both GABA

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and the inhibitory neuropeptide galanin and help to promote drowsiness and

sleep.

The waking state, on the other hand, is regulated by both cholinergic

and monoaminergic pathways. The cholinergic arousal pathway runs from

neurons in the pedunculopontine (PPT) and laterodorsal tegmental (LDT)

nuclei of the pons to relay nuclei in the thalamus. These neurons are also

involved in the generation of rapid eye movement (REM) sleep. The

monoaminergic pathways originate from their respective nuclei in the

brainstem— the noradrenergic locus coeruleus, the serotinergic raphe

nucleus, the histaminergic tuberomammillary nucleus, the dopaminergic

periaqueductal gray, and the glutamatergic parabrachial nucleus—and send

projections to the lateral hypothalamus and on to the cortex (figure 1).

There are reports of bilateral thalamic lesions in patients leading to

slowing of EEG background activity during wake, diminished slow wave

sleep, sleep spindles and K complexes during sleep, and disruption of the

endogenous circadian temperature nadir (Guilleminault et. al, 1993,

Montagna et. al, 2002), supporting the role of the thalamus in the regulation

of sleep and autonomic function. These findings are similar to what is seen

in patients with Fatal Familial Insomnia, a disorder of thalamic impairment,

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discussed in section 2.3.

Other work, however, has disputed the classic notion of the thalamus

as a relay center in the generation of wakefulness (Fuller et al, 2011). In this

study, researchers lesioned various neuroanatomical sites in rats and

demonstrated that basal forebrain lesions led to behavioral unresponsiveness

with slowing of EEG activity, whereas thalamic lesions had no effect on

either behavior or EEG activity, indicating that basal forebrain structures

may have more of an influence on the maintenance of wakefulness than

previously thought.

The third arousal promoting system consists of glutaminergic neurons

and hypocretin (otherwise known as orexin) neurons in the hypothalamus.

These neurons send projections to all of the monoaminergic nuclei to

simulate the release of their alerting neurotransmitters and are critical to the

maintenance of the waking state. Hypocretin neurons are also important in

autonomic control, and send projections to many ANS regulatory centers

including the periaqueductal gray, nucleus of the solitary tract, nucleus

ambiguus, and dorsal motor nucleus of the vagus nerve (Grimaldi, 2014).

There are many animal studies to suggest that orexin exerts influence on

several autonomic functions including heart rate and blood pressure

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regulation (Shirasaka et al., 1999), energy metabolism (Schuld et. al, 2000)

and gastrointestinal motility (Nozu et. al, 2011).

In the “flip-flop switch” model proposed by Saper, the neurons

promoting sleep and arousal inhibit each other, producing a condition

whereby one system turns off the opposing system when it gains control

(Saper, 2005). This model is common in electrical engineering and allows

for rapid transitions from sleep to wake and vice versa. If this system were

not present, we would drift gradually into and out of sleep without clear

transitions, instead of the more immediate state change that most of us

experience when falling asleep or awakening.

When it comes to the regulation of sleep and the waking state, as in

other homeostatic functions, the hypothalamus is an important

neuroanatomical area. It is organized into three functional zones: the

periventricular zone, the medial zone, and the lateral zone (figure 2). The

periventricular zone regulates neuroendocrine responses via the pituitary

gland. The medial zone regulates thermoregulation, response to stress, and

osmoregulation. The lateral zone regulates sleep and wake, hunger, and

reward responses. The modulatory hypocretin neurons mentioned earlier are

located in the lateral zone. The lateral zone and the periventricular zone also

contain autonomic neurons that send their efferent projections to the lateral

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medulla and the intermediolateral cell column (IML) of the spinal cord

(Saper, 2002). These efferent pathways help regulate vascular tone and

maintain our ability to undergo postural change without significant

alterations in blood pressure and heart rate.

The lateral medulla contains not only efferent autonomic pathways,

but many important afferent pathways as well. The baroreceptors,

chemoreceptors, cardiac receptors and respiratory receptors all send their

projections to the nucleus solitarius in the lateral medulla, via the

glossopharyngeal and vagus nerves (figure 3). These pathways are extremely

important in controlling breathing during sleep. They accomplish this task

via central pattern generators in the dorsolateral pons, the dorsal respiratory

group in the nucleus tractus solitarius, and the ventral respiratory group in

the lateral medulla (Feldman et al, 2006). They also rely on chemoreceptors

in the carotid body that send afferent projections to the nucleus solitarius.

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 The baroreceptors are stretch receptors located in the aortic arch and

carotid sinuses that help regulate our arterial blood pressure despite changes

in position and posture. Increasing blood pressure leads to increasing stretch

of these receptors, thereby increasing glutamatergic afferent tone to the

nucleus tractus solitaries in the brainstem. This inhibits sympathetic outflow

to cardiac and vasomotor smooth muscle and augments parasympathetic

cardiac outflow, resulting in reduced cardiac contractility, slowing of heart

rate, decreased peripheral vascular resistance, and an overall decrease in

blood pressure (Eckberg et al, 1992). Decreases in blood pressure produce

the opposite effect.

The role of the baroreceptor in sleep is complex; for a comprehensive

discussion we direct the reader to the review by Silvani et al. (2014). While

mild baroreceptor stimulation may inhibit arousal (Bridgers et al, 1985),

large increases or decreases in baroreceptor activity may facilitate arousal

(Cole et al, 1989). In addition, arousals themselves can modulate

baroreceptor tone. This bidirectional relationship has been likened to a

positive feedback loop involving the nucleus nucleus tractus solitarius,

adrenergic C1 neurons of the medulla, and the pontine parabrachial nucleus,

and enables more efficient transitions from sleep to wake and vice-versa

(Baust et al, 1967; Silvani et al, 2014).

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1.1 Neurotransmitters involved in the regulation of both sleep and

autonomic tone

Norepinephrine (NE) is released from the nerve terminals of post-

synaptic sympathetic neurons and is instrumental in the hyperadrenergic, or

“fight or flight” response. Norandrenergic neurons in the locus coeruleus

exhibit a reduced firing rate during non-rapid eye movement (NREM) sleep,

and an even further reduction during tonic REM sleep. The role of NE as an

alerting neurotransmitter is further supported by animal models

demonstrating levels of increased wakefulness with the infusion of alpha-1

and beta agonists (Lidbrink et al., 1974), and increased slow wave EEG

activity when these areas are pharmacologically inhibited (Berridge et al.,

2008).

This helps to explain the alerting effects of many stimulants, which

either increase NE release or inhibit NE reuptake. During phasic REM, when

the classic rapid eye movements are seen that give this stage of sleep its

name, NE neurons exhibit an increased firing rate and can produce dramatic

surges in blood pressure. These changes can be especially pronounced and

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quite dangerous in patients with obstructive sleep apnea, as detailed in

section 2.1.

Acetylcholine (ACH) is released from pre-synaptic and post-synaptic

parasympathetic neurons, as well as pre-synaptic sympathetic neurons.

Cholinergic neurons are responsible for regulating the waking state and the

REM state. These neurons are located in the basal forebrain and in the PPT

and LDT of the pons. Both of these areas exhibit higher firing rates during

waking and REM, producing a mixed frequency, desynchronized EEG.

Infusion of anticholinergics has been demonstrated to produce a more

synchronized EEG and promote drowsiness (Karczmar et al., 1970).

1.2 Autonomic physiology during sleep

As humans transition from wake to sleep, parasympathetic tone

increases, the respiratory rate slows, and breathing becomes more regular

(Somers et. al, 1993). The Boetzinger complex in the lateral medulla is

responsible for this reduction in respiratory rate, as well as respiratory sinus

arrhythmia, a normal physiologic phenomenon whereby heart rate

accelerates during inspiration to accommodate increased venous return, and

then decelerates during expiration. This same respiratory sinus arrhythmia is

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measured in the autonomic laboratory with heart rate variability during deep

breathing, a measurement of parasympathetic cardiovagal tone.

It is often difficult to measure autonomic fluctuations during sleep due

to the disruptive nature of beat-to-beat blood pressure monitors. Spectral

analysis of the RR interval is an indirect, noninvasive alternative. Spectral

analysis of heart rate variability is often referenced in in the literature as an

estimate of sympathetic and parasympathetic tone during sleep, otherwise

termed the sympathovagal balance. High-frequency RR signal (greater than

0.15 Hz) is associated with heightened parasympathetic tone, due to the

vagal-mediated respiratory sinus arrhythmia. Conversely, low-frequency RR

signal (0.04 to 0.15 Hz) may be associated with heightened sympathetic tone

(Malliani et al., 1991). A greater LF/HF ratio is suggestive of greater

sympathetic drive, while a lower LF/HF ratio is suggestive of greater

parasympathetic drive, although this correlation is not universally accepted.

Head up tilt or active standing, for instance, can produce a high LF/HF ratio.

Deep breathing in the supine position can produce a low LF/HF ratio.

As sleep progresses from stage 1 NREM sleep to the deeper stages of

2 and 3 NREM sleep, parasympathetic tone increases, resulting in a

progressive reduction in heart rate, blood pressure, and cardiac output (Van

de Borne et. al, 1996). Sympathetic tone simultaneously decreases, leading

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to a reduction in peripheral vascular resistance and arterial blood pressure.

The LF/HF ratio is quite low at this point. Baroreflex sensitivity increases,

further promoting a state of regular respiration and gas exchange. These

observations have contributed to the thought of NREM sleep as a state of

relative autonomic stability and metabolic recovery.

During sleep stage transitions, transient bursts of vagal tone may

occur. These bursts can augment physiologic respiratory sinus arrhythmia

and, in some cases, contribute to sinus pauses of significant duration

(Guilleminault, 1993). Heart rate reaches its nadir in stage 3 NREM sleep,

with a reduction of 20-23% compared to waking values (Dickerson et al.,

1993). During REM sleep, cholinergic neuronal discharges in the PPT and

LDT are responsible for the muscle atonia that inhibits body movement and

dream enactment. During phasic REM, when rapid eye movements indicate

an active dream state, sympathetic tone increases and parasympathetic tone

decreases. Blood pressure and heart rate may fluctuate dramatically, and

blood pressure can reach levels much higher than those of the waking state.

Arousals from either NREM or REM sleep can exacerbate these

elevations in blood pressure and heart rate. Sympathetic nerve activity, as

measured by microneurography in resting skeletal muscle, is typically higher

in phasic REM than the waking state (Somers et al., 1993). If frequent

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enough, these REM-related surges may carry over into the waking state,

leading to increased diurnal sympathetic tone and hypertension.

2. Primary Sleep Disorders and Autonomic Dysfunction

2.1 Sleep Disordered Breathing

Obstructive Sleep Apnea (OSA) is a common disorder, affecting an

estimated 5-10% of the general population (Young et al., 2002). In these

individuals, repeated apneas or hypopneas can impact the ANS and lead to

significant consequences. When a patient with OSA experiences an

obstructive respiratory event during sleep, pulmonary autonomic afferents

are largely inhibited due to the prolonged increase in negative intrathoracic

pressure, the result of inspiring against a closed or partially closed glottis

(Somers et al, 1995). As a result, hyperventilation is prevented,

baroreceptors are stimulated and sympathetic vasomotor tone increases,

leading to peripheral vasoconstriction (Lafranchi et al, 2011).

This frequently occurs in conjunction with hypoxemia, which

activates chemoreceptors in the carotid bodies and further exacerbates this

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vasoconstriction. Hypercapnea, as seen in patients with sleep-related

hypoventilation syndromes, stimulates central chemoreceptors in the

brainstem and increases sympathetic tone via a similar process (Somers et al,

1989). It is interesting to note that changes in the LF/HF ratio during sleep in

patients with sleep-related hypoventilation without OSA are similar to those

seen in patients with OSA (DePalma et al, 2013). This suggests that

hypoxemia, and not airway occlusion or intrathoracic pressure changes, may

be responsible for the autonomic dysfunction seen in patients with sleep

disordered breathing.

During an apnea, venous return increases. In addition, peripheral

vasoconstriction may persist for several seconds after the patient initiates a

recovery breath and resumes normal breathing, resulting in large blood

pressure surges. This process may repeat itself many times throughout the

course of the night, sometimes over a hundred times per hour in patients

with severe disease.

The apnea-induced hypoxia also triggers the activation of the so-

called “diving reflex,” a protective mechanism in all mammals whereby

cardiac vagal tone increases, resulting in transient bradycardia. This

mechanism helps preserve blood flow to the heart and brain while limiting

cardiac oxygen demand. In susceptible individuals, however, the diving

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reflex can trigger sinus pauses and bradyarrhythmias such as AV block

(Guilleminault et al., 1983). When breathing resumes, cardiac output

increases and sympathetic tone remains elevated, predisposing susceptible

individuals to tachyarrhythmias.

Because of the progressive parasympathetic dominance during NREM

sleep, a normal 24-hour BP pattern consists of a NREM systolic blood

pressure reduction of greater than or equal to 10% of daytime values,

commonly referred to as “dipping” (van de Borne et al., 1994). Lack of

systolic dipping, or “non-dipping,” has been associated with increased

cardiovascular and cerebrovascular mortality (Fagard et al., 2008). Patients

with OSA can also exhibit “reverse-dipping,” whereby blood pressure

increases during sleep, indicative of increased sympathetic tone. Patients

with OSA have higher levels of muscle sympathetic nerve activity as

measured by microneurography, as well as increased catecholamine levels

(Narkiewicz et al., 2003). These findings were demonstrated not only when

the patients were asleep, but also while awake, indicating that this adrenergic

drive persists and may contribute to the increased incidence of hypertension

seen in these patients. In addition, there is evidence that patients with OSA

have diminished baroreceptor reflex sensitivity, which has also been

implicated in the pathophysiology of hypertension (Correlli et al, 1994). For

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an excellent summary on the topic of hypertension and sleep, please see the

review by Pepin and colleagues (2014).

Several large, population-based cohort studies have established OSA

as an independent risk factor for hypertension (Peppard et al., 2000),

cardiovascular disease (Shahar et al., 2001), atrial fibrillation and ischemic

stroke (Redline et al, 2010; Marin et al., 2005). Most cardiovascular and

cerebrovascular events occur in the early morning hours, either out of sleep

or shortly after awakening. This may be related to the increased sympathetic

tone in the early morning hours, as the frequency and duration of phasic

REM periods increase.

While there are other features of an apnea that may contribute to this

increased vascular risk, such as hypoxia (Malhotra et al, 2009), increased

intrathoracic and intramural cardiac pressure (Bradely et. al, 2001), and a

heightened inflammatory cytokine response (Mohsenin, 2014), increased

sympathetic drive likely plays a significant role (figure 4). Treatment with

CPAP has been demonstrated to improve cardiac autonomic modulation

(Khoo et al, 2012) and reduce sympathetic activity, as measured by

microneurography (Waravdekar, 1996) and plasma catecholamines

(Narkiewicz et al, 1999). It has also been demonstrated to reduce the

severity of hypertension (Pedrosa et al, 2013) and recurrent ischemic stroke

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(Martinez et al, 2012), although it has failed to demonstrate a consistent

reduction in lipid levels, insulin resistance or inflammatory markers (Jullian-

Desayes et al., 2015).

For these reasons, every patient with cardiovascular or

cerebrovascular disease should be queried for symptoms of OSA, and every

patient with OSA should be treated to reduce their risk of cardiovascular and

cerebrovascular disease. There are several validated questionnaires that have

been developed as screening tools for this purpose, including the STOP-

BANG (Chung et al, 2008, Figure 5.) and Berlin questionnaires (Netzer et

al, 1999).

Clinical Highlights: OSA

OSA may lead to increased sympathetic tone and diminished

baroreceptor sensitivity, thus increasing risk of hypertension,

cardiovascular and cerebrovascular disease.

Sympathetic activation and hypoxia can increase the risk of

tachyarrhythmias such as atrial fibrillation.

Hypoxia and the diving reflex can increase the risk of

bradyarrhythmias such as heart block.

Treatment of OSA may reduce the risk of hypertension,

cardiovascular and cerebrovascular disease.

Every patient with cardiovascular and cerebrovascular disease should

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be screened for OSA.
2.2 Insomnia and Sleep Deprivation

Insomnia is even more common that OSA, effecting an estimated 6%

to 18% of the general population (Ohayon et al., 2002). Insomnia is defined

by the American Academy of Sleep Medicine as difficulty falling asleep,

difficulty staying asleep, early morning awakenings, or nonrestorative or

nonrefreshing sleep, in conjunction with daytime impairment (International

Classification of Sleep Disorders, 3rd ed, American Academy of Sleep

Medicine, Darien, IL 2014).

Like patients with OSA, many patients with insomnia are also non-

dippers (Lanfranchi et al., 2009). In addition, frequent arousals, either

spontaneous or secondary to an underlying sleep disorder, can result in

increased sympathetic tone. There is a typical cardiac response observed

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during an arousal: an initial tachycardia, which often precedes the

electrocortical arousal by several seconds, followed by bradycardia. If the

arousals are frequent enough, the elevation in sympathetic tone can persist

long after the patient has returned to sleep (Blasi et al., 2003).

When compared to good sleepers, patients with insomnia have a

greater incidence of hypertension (Suka et al., 2003; Gangwisch et al., 2006;

Vgontaz et al., 2009). In a large population-based, cross-sectional study of

1,741 patients (Vgontaz), a polysomnographically determined sleep time of

less than five hours was associated with the presence of hypertension. This

association remained after adjusting for age, race, gender, smoking, obesity,

diabetes, alcohol consumption, depression, and other sleep disorders such as

OSA and PLMD. Interestingly, this association was nearly as high as in

those patients with OSA (defined in this study as an apnea-hypopnea index

of ≥ 5). Baroreceptor tone also reaches a higher set point after sleep

deprivation (Carter et al, 2012) and may play a role in the pathophysiology.

Another study evaluating heart rate variability in insomnia patients

demonstrated an elevated LF/HF ratio compared to good sleepers,

suggesting increased sympathetic activity (Bonnet et al., 1998), however

these results have not been replicated in other studies. Several studies have

shown that patients with insomnia have an elevated pre-ejection period

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(PEP) during sleep (de Zambotti et al, 2013; de Zambotti et al, 2011). This

index is inversely related to cardiac beta-adrenergic sympathetic autonomic

activity.

When viewed in aggregate, these studies all suggest increased

nocturnal cardiac sympathetic drive in insomnia patients. No one is more

acutely aware of this phenomenon than patients with insomnia, who

frequently describe a sensation of generalized hyperarousal that prevents

them from falling asleep even in the setting of exhaustion, a presentation

referred to in the sleep clinic as “tired but wired.”

The theory of hyperarousal is supported by several studies that have

examined functional imaging and EEG analysis in these patients. PET

imaging in chronic insomnia patients during sleep has demonstrated

increased activation and hypermetabolism in the arousal networks of the

hypothalamus and brainstem, as well as their efferent projections in the

medial prefrontal cortex and amygdala. (Nofzinger et al., 2004). EEG

frequency analysis has demonstrated that these patients have increased beta

(14-35 Hz) and gamma (35-45 Hz) activity, frequencies typically associated

with the cortical activity of the waking state. (Perlis et al., 2001). Many

patients with sleep-state misperception, or “paradoxical insomnia” may in

fact have increased beta and gamma frequencies during sleep. The

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hyperarousal model, with its focus on heightened hypothalamic-pituitary-

adrenal tone, increased catecholamine secretion, and excessive cortical

activity during wake and sleep, may provide a window into the

understanding of the autonomic complaints in these patients. Treatment with

either medication or cognitive behavioral therapy may help reduce the risk

of hypertension and hyperarousal.

There is growing evidence that sleep-deprived patients without

insomnia also exhibit signs of autonomic impairment and are at greater risk

of developing hypertension, even if young and otherwise healthy. Sleep

deprivation can result in increased sympathetic drive, regardless of the

underlying etiology. In a study of male workers who were sleep deprived,

working overtime and sleeping only four hours a night induced higher

daytime blood pressure the following day, when compared to a normal

working day and allowing for eight hours of sleep (Tochikubo et al., 1996).

There were also higher LF components of heart rate variability and increased

urinary excretion of NE in these patients. Sleep deprivation has been linked

to increased daytime catecholamine levels (Lusardi et al., 1996), and

frequent arousals have been associated with increases in plasma cortisol

levels (Späth-Schwalbe et al., 1991), however researchers have not been able

to consistently replicate these findings in insomnia patients.

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 Clinical Highlights: Insomnia and Sleep Deprivation

Patients with insomnia may develop increased diurnal sympathetic drive, leading

to the clinical presentation of hyperarousal.

Compared to good sleepers, patients with insomnia have a greater risk of

developing HTN.

Sleep deprivation may also results in increase sympathetic drive and increased

risk of HTN.

Treatment of insomnia, with either medication or cognitive behavioral

2.3
therapy, may help reduce risk of HTN and hyperarousal.

Pri

on Disorders

Although Fatal Familial Insomnia (FFI) is not a diagnosis commonly

encountered in the sleep clinic, it serves as an illustrative disorder that

affects both sleep and autonomic function. FFI is a rare autosomal dominant

prion disease linked to a missense mutation of the prion protein gene.

Patients with FFI develop spongiform degeneration of the mediodorsal and

anterior thalamic nuclei, areas that help regulate sleep and autonomic control

(Lugaresi et al., 2011). Insomnia is an early feature of the disease, followed

by apathy, derealization, and a dream-like state referred to as oeneric stupor

(Lugaresi et al., 2011). Autonomic instability is prominent and includes

hypertension, tachycardia, elevated body-core temperature and hyperhidrosis,

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all features of a hyperadrenergic state. The combination of insomnia,

sympathetic activation and oeneric stupor is referred to as agrypnia excitata

syndrome. Patients become “non-dippers,” losing the physiologic nocturnal

blood pressure reduction during sleep (Montagna et al., 2003). Sympathetic

tone is elevated during wakefulness, as measured by resting SNA (Donadio

et al., 2009). Serial 24-hour monitoring of hormonal and catecholamine

levels in these patients has revealed elevated plasma concentrations of

cortisol and NE (Portaluppi et al., 1994).

PSG recordings have demonstrated a progressive reduction and

disappearance of spindles, K complexes, and slow wave sleep, indicating a

disruption in the thalamocortical circuits necessary for the generation of

these electrographic phenomena (Lugaresi et al., 2011). The thalamic

spongiform degeneration and reactive gliosis that occurs in these patients is

thought to disrupt connections to the limbic pre-frontal cortex, hypothalamus

and brainstem, areas that influence both sleep and autonomic control.

Plasma melatonin concentrations diminish as the disease progresses, leading

to complete disruption of circadian rhythms (Portaluppi et al., 1994). The

mean age at onset is 51 years of age, and death typically occurs within 8–

72 months.

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 It has also been demonstrated that patients with Creutzfeldt–Jakob

disease, another prion disorder, have diminished heart rate variability during

sleep (DePalma et al, 2014). PrPSc, the abnormal prion protein that

accumulates in these diseases, has been demonstrated in regions that are

Clinical Highlights: Prion Disorders

Autonomic impairment is secondary to deposition of prion protein in regions of the brain

that control autonomic function, such as the thalamus and lateral medulla.

Patients with FFI may present with agrypnia excitata, the combination of insomnia,

sympathetic activation and oeneric stupor

Loss of sleep spindles, K complexes, and slow wave sleep may occur, indicating disruption

of thalamocortical circuits important to help to regulate sleep and autonomic control.

important in regulating autonomic activity, such as the lateral medulla, likely

playing a role in the pathophysiology.

2.4 Periodic Limb Movement Disorder and Restless Legs Syndrome

Periodic limb movements (PLMs) are repetitive triple flexion

responses involving the great toe, ankle, and knee that occur out of sleep,

sometimes leading to arousals. If a patient exhibits frequents PLMs during

sleep and symptoms of daytime impairment are present, a diagnosis of

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periodic limb movement disorder (PLMD) may be considered. The

autonomic arousal response discussed earlier, that of a rapid rise in heart rate

and arterial blood pressure followed by a rapid bradycardia and a return of

blood pressure to baseline values, has been demonstrated prior to the onset

of PLMs during sleep. In fact even without an arousal, PLMs have been

associated with this autonomic cardiovascular response (Sforza et al., 1999),

although the magnitude of the response is greater when an arousal is present.

In addition, bilateral PLMs produce a greater response than do unilateral

PLMs (Ferri et al., 2007). This has led to the theory that the autonomic

cardiovascular response may be related to the degree of central activation

rather than the somatomotor response of the leg movements themselves

(Pennestri et al., 2007). Other studies have failed to identify differences in

HRV between patients with PLMs and control subjects without leg

movements or arousals, leading to the theory that PLMS may result from the

loss of subcortical inhibition to pacemaker cells in the spinal cord or

brainstem that have phasic control of autonomic, motor and arousal

networks (Palma et al., 2014).

Some researchers have proposed a progressive sequence of the arousal

response that begins with activation of the ANS, followed by EEG

synchronization, then EEG desynchronization and eventually awakening

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(Sforza et al., 1999). As with other disorders of frequent arousal and sleep

fragmentation, over time this may lead to greater diurnal sympathetic

activity. Like patients with OSA and insomnia, patients with PLMD have

been noted to have an increased risk of cardiovascular disease (Innes et al.,

2012).

Restless Legs Syndrome (RLS) is a common disorder affecting an

estimated 5-10% of the population (Ohayon et al., 2012). It is common for

patients with RLS to have frequent PLMs during sleep. Unlike PLMD,

however, RLS is a clinical syndrome with four cardinal features that include

an urge to move the legs, symptoms that worsen with rest or inactivity, are

relieved with movement, and occur predominantly in the evening hours

(International Classification of Sleep Disorders, 3rd ed, American Academy

of Sleep Medicine, Darien, IL 2014).

In one study, patients with RLS reported more autonomic symptoms

than controls (Shneyder at al., 2012). The most commonly reported

symptoms were sialorrhea, constipation, early satiety, heat intolerance and

orthostatic intolerance. In another study, patients with RLS reported a higher

incidence of erectile dysfunction (Gao et al., 2010). More recently, Izzi and

colleagues performed autonomic testing on a small group of RLS patients.

When compared to controls, RLS patients exhibited higher supine blood

Page 27 of 63
pressures, as well as a blunted compensatory heart rate response on ten-

minute head up tilt, suggestive of mild sympathetic adrenergic impairment

(Izzi et al., 2014). Other studies have failed to demonstrate an association

between RLS and HTN (Gianni et al., 2014).

While the pathophysiology of RLS is yet to be elucidated and is likely

multifactorial, one theory involves a reduction in dopaminergic outflow to

the preganglionic sympathetic neurons in the dorsal horn of the spinal cord

(Walters A, 2009). Dopamine inhibits preganglionic sympathetic neurons,

therefore a reduction in dopamine may in turn increase sympathetic outflow.

PLMs are present in approximately 80-90% of patients with RLS, however

not all patients with PLMs have symptoms of RLS.

Although PLMs may play some role in autonomic impairment, the

extent of this impairment and it’s association with RLS is yet to be

determined. In addition, it must be remembered that RLS can result in

significant insomnia, which by itself can lead to increased sympathetic drive.

Clinical Highlights: PLMD and RLS

PLMs can trigger a rapid rise in heart rate and arterial blood pressure followed by

bradycardia and a return of blood pressure to baseline values prior to the onset of PLMs

during sleep. This response can occur without an arousal, though it is more pronounced

if an arousal occurs.

 Patients with PLMD have been noted to have an increased risk of cardiovascular disease.

Patients with RLS frequently report symptoms of autonomic dysfunction.

Page 28 of 63
2.5 Narcolepsy

Studies evaluating autonomic function in patients with narcolepsy

have yielded conflicting results. Most of these studies have focused on

patients with cataplexy, or type-I narcolepsy in more recent studies using the

ICSD-3 nomenclature. Some studies have demonstrated an increased LF/HF

ratio during sleep (Grimaldi et al., 2010), indicating increased sympathetic

drive, however other studies have demonstrated findings consistent with

reduced sympathetic drive (Fronczek et al., 2008). Several studies have

indicated that narcolepsy patients are more likely to be non-dippers

(Donadio et al., 2014, Dauvilliers, 2012), suggesting either increased

sympathetic drive or parasympathetic withdrawal. This phenomenon has

also been demonstrated in hypocretin-deficient mice (Bastianini et al., 2011).

Another study found that narcolepsy patients had elevated heart rates during

all stages of sleep, along with a blunted heart rate response to awakening

when compared to controls, though no difference in LF/HF ratios (Van der

Meijden et al., 2014). Ohayon found a greater prevalence of cardiovascular

disease and hypertension in narcolepsy patients (2013). One possible

Page 29 of 63
explanation for this is a lack of blood pressure and heart rate dipping during

sleep, which has been associated with greater cardiovascular risk in other

sleep disorders such as OSA.

In a more recent study, researchers demonstrated that patients with

type I narcolepsy have lower sympathetic burst activity during wakefulness

than controls, as measured by microneurography (Donadio et al., 2014). As

expected, these patients also had reduced resting heart rate and blood

pressure. Interestingly, the degree of this reduction in sympathetic tone was

directly correlated with the degree of hypocretin-1 deficiency in the cerebral

spinal fluid.

Regardless of whether patients with type I narcolepsy have increased

or decreased sympathetic drive, the autonomic dysfunction in these patients

likely stems from the loss of hypocretin neurons and their modulating effect

on the ANS. Hypocretin cell bodies in the hypothalamus send projections to

ANS cell bodies in the IML of the spinal cord. The infusion of intrathecal

hypocretin in animals has been demonstrated to increase sympathetic drive

(Antunes et al., 2001, Shirasaka et al., 1999) and resting blood pressure in a

dose dependent manner (Matsamura at al., 2001). Thus it is conceivable that

patients with a reduction or absence of circulating hypocretin levels would

have a lower resting sympathetic tone, although this has not been firmly

Page 30 of 63
established. It is interesting to note that while PLMs are quite common in

patients with narcolepsy (Dauvilliers at al., 2007), the patients in this study

demonstrated decreased, not increased, sympathetic drive.

Clinical Highlights: Narcolepsy

 Data on autonomic dysfunction in narcolepsy is conflicting, with some studies indicating

increased sympathetic drive and others decreased sympathetic drive.

 The autonomic imbalance in narcolepsy patients is likely directly related to the loss of

hypocretin cells in the hypothalamus.

 Narcolepsy patients are more likely to be non-dippers, a phenomenon that has been

associated with greater cardiovascular risk in other sleep disorders.

risk.

2.6 REM Behavior Disorder


Rapid-Eye Movement Behavior Disorder (RBD) is a condition

whereby a patient loses the protective muscle atonia that normally occurs

during REM sleep. These patients are thereby free to act out their dreams,

many times with injurious consequences. Common manifestations include

punching, kicking, flailing about, or falling out of bed. Dream recall is

common.

The association between RBD and neurodegenerative disease has

Page 31 of 63
been well established, with an estimated 80% of patients with idiopathic

RBD (iRBD) eventually developing some form of alpha synucleinopathy

such as Parkinson’s disease (PD), dementia with Lewy bodies, or multiple

system atrophy (Iranzo et al., 2013; Postuma et al., 2009; Schenck et al.,

2013; Boeve et al., 2013). In fact, RBD is probably the strongest non-motor

predictor of future disease, with an estimated median latency between RBD

and motor symptoms of 12 to 14 years (Postuma et. al, 2012).

Like RBD, autonomic dysfunction is an early manifestation of disease

in these patients, commonly occurring in the prodromal period (Boeve,

2013). This is likely due to the proximity of the cholinergic REM nuclei and

the autonomic nuclei in the brainstem, as discussed in section 1. In the Braak

model of neurodegeneration, these nuclei become impaired before the motor

nuclei are affected, as the deposition of alpha synuclein progresses in a

rostral-caudal fashion from the lower brainstem to the cortex (Braak et. al,

2003). Although autopsy studies of iRBD patients are limited, in several

cases Lewy bodies were discovered in the mesencephalopontine areas

involved in REM atonia, as well as the dorsal nucleus of the vagus nerve

(Uchiyama et al, 1995; Boeve at al, 2007).

Symptoms of autonomic impairment are common in patients with

iRBD. In a large multicenter case-control study, 318 patients with iRBD

Page 32 of 63
were administered the Scale for Outcomes in PD-Autonomic (SCOPA-

AUT), a standardized 25-item autonomic questionnaire that addresses

several domains including gastrointestinal, urinary, cardiovascular,

thermoregulatory, pupillomotor, and sexual function (Ferini-Strambi et. al,

2014). Patients with iRBD reported more impairment than controls, with

the greatest deficits in gastrointestinal, urinary, and cardiovascular function.

There is also evidence that these patients have a higher conversion rate to

clinically apparent neurogenerative disease (Postuma et. al, 2015). In

addition, within the alpha-synucleinopathies, the presence of RBD seems to

be correlated with a greater degree of autonomic dysfunction. (Postuma et.

al, 2012).

Patients with iRBD have reduced heart rate variability during REM

sleep (Lanfranchi et. al, 2007), and a blunted heart rate response to PLMs

when compared to patients with RLS (Fantini et al., 2002). They may also

have more significant systolic blood pressure falls on active stand. Postuma

and colleagues demonstrated an average systolic blood pressure reduction of

15.2 mmHg in these patients on active stand tests, compared to 3.7 mmHg in

age-matched controls (Postuma et al., 2009). While most patients reported

symptoms of orthostatic intolerance, this blood pressure change was not

significant enough to meet criteria for orthostatic hypotension.

Page 33 of 63
 This data was corroborated by Frauscher and colleagues, who

performed autonomic testing on iRBD patients and compared them to both

controls and to patients with PD (2011). While patients with iRBD did not

demonstrate orthostatic hypotension on tilt testing, they had slightly greater

blood pressure falls on active stand when compared to controls. In addition,

the Valsalva ratio, an indicator of cardiovagal function, was significantly

lower in iRBD patients when compared to healthy controls.

Patients with iRBD have evidence of post-ganglionic cardiac

sympathetic denervation as measured by 123I-MIBG scintigraphy

(Miyamoto et. Al, 2006), further supporting the concept of prodromal

autonomic impairment in these patients. In addition, this cardiac sympathetic

denervation may be more closely associated related to the presence of RBD

than the presence of alpha-synucleinopathy. One study found that patients

with PD and RBD demonstrated reduced heart rate variability during REM

and NREM sleep, while PD patients without RBD were no different from

controls in demonstrating normal cardiac variability (Postuma et al., 2011).

This finding was very similar to findings by the same group who found

reduced heart rate variability in patients with iRBD, regardless of whether

they went on to develop neurodegenerative disease (Postuma et al., 2010).

Regardless of the pathophysiology of autonomic impairment in

Page 34 of 63
patients with RBD, it is a clinical feature that appears many years before the

motor manifestations of neurodegenerative disease, thus providing early

identification of patients at risk of developing a clinically significant

Clinical Highlights: REM Behavior Disorder

 Up to 80% of patients with iRBD will eventually develop some form of alpha

synucleinopathy, with a median latency of 12 to 14 years between between iRBD

symptoms and the development of motor symptoms.

 iRBD has been associated with reduced heart rate variability during sleep, a sign of

cardiac sympathetic denervation.

Autonomic dysfunction in RBD patients with alpha synucleinopathies is common,

although it is unclear if this dysfunction is more closely related to pathology of RBD or

the alpha synucleinopathy itself.

synucleinopathy. This early identification may provide a potential window

for disease modifying therapies, should such therapies become available to

clinicians
 in the future.

Conclusions

The autonomic nervous system is integrally related to sleep initiation,

maintenance, and disruption. When such disruption becomes frequent or

Page 35 of 63
chronic, autonomic impairment may follow. In the short term, such

autonomic impairment may lead to increased sympathetic drive and a

sensation of hyperarousal, further perpetuating the sleep disturbance. If

sustained, this impairment may result in significant morbidity and even

mortality, especially in patients with OSA. Because of this association, any

patient presenting with autonomic dysfunction should be queried about their

sleep patterns, and close attention should be paid to symptoms of autonomic

dysfunction in patients with sleep disorders.

Acknowledgements

I would like to thank Dr. Ronald Postuma for his help in reviewing this

manuscript.

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Figure 1. Cell populations of arousal systems.

A major input to the relay and reticular nuclei of the thalamus (yellow pathway) originates from cholinergic

(ACh) cell groups in the upper pons, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT).

These inputs facilitate thalamocortical transmission. A second pathway (red) activates the cerebral cortex to

facilitate the processing of inputs from the thalamus. This arises from neurons in the monoaminergic cell

groups, including the tuberomammillary nucleus (TMN) containing histamine (His), the A10 cell group

containing dopamine (DA), the dorsal and median raphe nuclei containing serotonin (5-HT), and the locus

coeruleus (LC) containing noradrenaline (NA). This pathway also receives contributions from peptidergic

neurons in the lateral hypothalamus (LHA) containing orexin (ORX) or melanin-concentrating hormone

(MCH), and from basal forebrain (BF) neurons that contain γ-aminobutyric acid (GABA) or ACh. It should

be noted that ACh and NA cell populations are also involved in autonomic relay pathways. Reprinted by

Permission from Macmillan Publishers, Ltd: Saper CB et al., 2005. Hypothalamic regulation of sleep and

circadian rhythms. Nature. 437, 1257-63.

Figure 2. Functional zones of the hypothalamus.

The periventricular zone regulates neuroendocrine responses via the pituitary gland. The medial zone

regulates thermoregulation, response to stress, and osmoregulation. The lateral zone regulates sleep and

wake, hunger, and reward responses. Reprinted by Permission from Macmillan Publishers, Ltd: Benarroch,

E.E., 1993. The central autonomic network: functional organization, dysfunction, and perspective. Mayo

Clin Proc. 68, 988-1001.

Figure 3. Areas of the lateral medulla involved in tonic and reflex control of vasomotor, cardiovagal,

and respiratory functions. Reprinted by Permission from Macmillan Publishers, Ltd: Benarroch, E.E.,

1993. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin

Proc. 68, 988-1001.

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Figure 4. Many possible factors that contribute to increased cardiovascular risk in OSA patients.

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in sleep apnea with particular emphasis on children. Front Neurol. 3, 7.

Figure 5. STOP-BANG questionnaire to screen for OSA in patients with stroke or transient ischemic

attack. From: Chung, F., Yegneswaran, B., Liao, P., Chung, S.A., Vairavanathan, S., Islam, S., Khajehdehi,

A., Shapiro, C.M., 2008. STOP questionnaire: a tool to screen patients for obstructive sleep apnea.

Anesthesiology. 108, 812-21.

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