Autonomic dysfunction in primary sleep disorders

Accepted Manuscript Title: Autonomic dysfunction in primary sleep disorders Author: Mitchell G. Miglis PII: DOI: Reference:

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

To appear in:

Sleep Medicine

Received date: Revised date: Accepted date:

6-7-2015 8-9-2015 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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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.

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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: [email protected]

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 postsynaptic 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 socalled “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 (JullianDesayes 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 STOPBANG (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 Page 18 of 63

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 nondippers (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-pituitaryadrenal 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 therapy, may help reduce risk of HTN and hyperarousal.

2.3 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

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pressures, as well as a blunted compensatory heart rate response on tenminute 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.

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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

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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

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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

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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

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were administered the Scale for Outcomes in PD-Autonomic (SCOPAAUT), 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.

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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

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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

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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. From: Hakim, F., Gozal, D., Kheirandish-Gozal, L., 2012. Sympathetic and catecholaminergic alterations 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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