Autonomic dysfunction in sleep disorders …

Sleep Disorders

Updated 03.23.2024
Released 07.21.2003
Expires For CME 03.23.2027

Autonomic dysfunction in sleep disorders

Authors: Giovanna Calandra-Buonaura MD PhD, Francesca Baschieri MD

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Editor: Antonio Culebras MD FAAN FAHA FAASM

Autonomic dysfunction in sleep disorders

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Introduction

Overview

Sleep and the autonomic nervous system are closely related from an anatomical, physiological, and neurochemical point of view. In this article, the authors describe the clinically relevant dysfunctions of cardiovascular and respiratory autonomic control caused by or associated with sleep disorders. In particular, the authors discuss the association between sleep-wake cycle derangement and autonomic sympathetic overactivity in fatal familial insomnia; the autonomic dysfunctions and the genetic discoveries in congenital central alveolar hypoventilation syndrome; the abnormalities of cardiovascular autonomic control in obstructive sleep apnea and narcolepsy type 1; and the relationship among REM sleep behavior disorder, cardiovascular autonomic dysfunction, and neurodegenerative disease. The autonomic dysfunction, particularly when involving cardiovascular or respiratory control, has a negative impact on prognosis of the associated sleep disorder and may represent a risk factor for the development of other chronic diseases or for life-threatening events. A prompt diagnosis of these autonomic dysfunctions is, therefore, of crucial importance to choose the proper therapeutic approach and treat the risk factors that could severely influence the prognosis.

Key points

	• Sleep and the autonomic nervous system are closely related from an anatomical, physiological, and neurochemical point of view.
	• Sleep disorders may cause or be associated with clinically relevant autonomic dysfunctions.
	• Fatal familial insomnia, congenital central alveolar hypoventilation syndrome, obstructive sleep apnea, narcolepsy type 1, and REM sleep behavior disorder are associated with clinically relevant autonomic dysfunctions involving cardiovascular and respiratory control.
	• Dysfunctions of cardiovascular and respiratory autonomic control have a significantly negative impact on prognosis of the associated sleep disorder and may represent a risk factor for the development of other chronic diseases or for life-threatening events.

Historical note and terminology

The autonomic nervous system controls vital involuntary body functions, such as circulation, respiration, thermoregulation, neuroendocrine secretion, and gastrointestinal and genitourinary functions, through several interconnected areas of the central nervous system belonging to the central autonomic network and two efferent pathways: the sympathetic and parasympathetic nervous systems (Table 1). These efferent systems are composed of preganglionic neurons in the brainstem and spinal cord and postganglionic neurons that form synapses with the target organs (18). There is an intimate relationship between the autonomic nervous system and sleep from an anatomical, physiological, and neurochemical point of view. However, in the past, it was commonly assumed that autonomic regulation remained unchanged across behavioral states, and the concept of a state-dependent regulation of the autonomic nervous system has been addressed only recently. Coccagna and colleagues first understood the importance of recording autonomic parameters during sleep in clinical medicine and described the dramatic changes in systemic and pulmonary blood pressure associated with apneas and resuming of breathing in patients with obstructive sleep apnea (30; 93). Because the discovery that an abnormal blood pressure behavior during sleep is an important risk factor for cerebrovascular and cardiovascular disease, many studies have evaluated changes in autonomic nervous system activity associated with sleep disorders (23).

Table 1. Main Effects of the Sympathetic and Parasympathetic Control on the Target Organs

Organ	Sympathetic control	Parasympathetic control
Pupil	Dilation	Constriction
Blood Vessel (arterioles)	Constriction	none
Lung	Bronchodilation	Bronchoconstriction
Heart	Increase heart rate	Decrease heart rate
	Increase myocardial contractility	Decrease myocardial contractility
Gastrointestinal tract	Decrease motility	Increase motility
Kidney	Decrease output	none
Bladder	Relax detrusor	Relax sphincter
	Contract sphincter	Contract detrusor
Penis	Ejaculation	Erection
Sweat gland	Secretion	Palmar sweating
Piloerection	Increase	none
Lacrimal gland	Slight secretion	Secretion
Parotid gland	Slight secretion	Secretion
Submandibular gland	Slight secretion	Secretion

Clinical manifestations

Presentation and course

	• Sleep disorders may be associated with autonomic dysfunction in some neurologic conditions.
	• Some sleep disorders may cause autonomic dysfunction.
	• Autonomic dysfunction may represent a risk factor for worse prognosis.

A dysfunction of autonomic control results from an impaired balance between sympathetic and parasympathetic activity, which could depend on under-activity (failure) or over-activity of one or both of the effector systems. The clinical consequences are related to the nature of the dysfunction; for example, a failure of sympathetic control of the cardiovascular system causes orthostatic hypotension, whereas a parasympathetic failure manifests with fixed heart rate.

The autonomic dysfunction may, in turn, be due to a functional impairment or damage of central autonomic areas, postganglionic sympathetic and parasympathetic neurons, or medullary cardiovascular and respiratory reflexes (ie, baroreceptor and chemoreceptor reflexes).

Some neurologic and general medical disorders are associated with both autonomic dysfunctions and sleep disturbances, which result from the same pathophysiological mechanism. Conversely, some sleep disorders may cause autonomic dysfunction. However, the causal relationship between autonomic dysfunction and sleep disorders in certain conditions still needs to be established. It has been demonstrated that the autonomic disorder, particularly when involving cardiovascular or respiratory control, not only impairs a patient’s quality of life but also has a significantly negative impact on prognosis of the associated sleep disorder and may represent a risk factor for the development of other chronic diseases or for life-threatening events.

Clinical manifestations of cardiovascular autonomic dysfunction include tachycardia, bradycardia, paroxysmal or sustained hypertension, and orthostatic hypotension (58), which is frequently associated with supine hypertension (46). Hypoventilation, irregular breathing rate, central apneas, and Cheyne-Stokes respiration are the main harmful clinical manifestations of impaired autonomic respiratory control (Table 2) (102; 16).

In the present article, we describe the clinical presentation, supposed pathogenetic mechanisms, and the diagnostic and prognostic implications of cardiovascular and respiratory autonomic dysfunctions associated with the following sleep disorders: fatal familial insomnia, congenital central alveolar hypoventilation syndrome, obstructive sleep apnea syndrome, narcolepsy type 1, and REM sleep behavior disorder (02).

Table 2. Primary Clinical Manifestations of Autonomic Control Dysfunction

Pupil	Abnormal miosis Abnormal mydriasis
Cardiovascular	Orthostatic hypotension Supine hypertension Paroxysmal hypertension Bradycardia Tachycardia

Respiratory	Hypoventilation Central apneas Irregular breathing rate Cheyne-Stokes respiration
Urinary	Urinary frequency Nocturia Urinary urgency Incomplete bladder emptying Incontinence
Sexual	Erectile failure Priapism Retrograde ejaculation Ejaculatory failure
Sudomotor	Hypohidrosis Anhidrosis Hyperhidrosis Heat intolerance Hyperpyrexia

Fatal familial insomnia

	• Sympathetic overactivation and progressive sleep loss characterize agrypnia excitata, which is the clinical hallmark of fatal familial insomnia.
	• Agrypnia excitata is the manifestation of thalamic dysfunction.
	• Fatal familial insomnia is a model for understanding the role of the thalamus in sleep regulation and autonomic control.

Fatal familial insomnia is a rare autosomal-dominant prion disease linked to a missense mutation at codon 178 of the prion protein gene located on chromosome 20 co-segregating with methionine at codon 129, the site of a common methionine-valine polymorphism. Clinical hallmark of the disease is agrypnia excitata syndrome, characterized by a progressive and untreatable sleep loss associated with autonomic sympathetic and motor over-activation and with episodes of a peculiar oneiric behavior (oneiric stupor) (65; 95). These are still the cardinal features of fatal familial insomnia, as confirmed by a recent proposal for new diagnostic criteria that identified sleep disorders in the form of agrypnia excitata and progressive sympathetic symptoms (hypertension, tachycardia, irregular breathing, hyperthermia, sweating, and weight loss) as main core clinical features, together with neuropsychiatric symptoms, which also best differentiate this condition from other prion disorders (29). Somatomotor abnormalities (eg, pyramidal signs, myoclonus, ataxia, dysarthria, dysphagia, gait disorders, parkinsonism, bulbar syndrome) also occur with variable latency and degree during the course of the disease (147). The disease starts on average between the fourth and sixth decade of life, most commonly between 51 to 60 years, and is uniformly fatal.

Polysomnographic recordings show a progressive wake-sleep cycle derangement characterized by drastic reduction of total sleep time with disappearance of physiological sleep figures (sleep spindles and K complexes) and of delta sleep activities. Synchronized sleep is completely abolished later in the course of the disease, whereas short episodes of REM sleep persist (95). Cardiovascular and respiratory autonomic signs and symptoms are prominent and include tachycardia and hypertension, irregular respiratory rhythm or respiratory pauses, and in later disease stages, persistent tachypnea and labored breathing that lead to respiratory failure or abnormal respiratory rhythm. Increased sweating, urinary urgency, sexual impotence, constipation, and diarrheic bowel can also be present (08). Longitudinal 24-hour polysomnographic and autonomic monitoring in these patients document that the progressive wake-sleep cycle derangement is associated with higher heart rate, blood pressure, breathing rate, and body core temperature values compared to controls. The study of the circadian rhythms of cardiovascular parameters show that blood pressure and heart rate maintain a 24-hour rhythmicity even after the disappearance of sleep, until terminal stages of the disease. Interestingly, however, the physiological nocturnal fall of blood pressure values is lost early in the disease course, whereas nocturnal bradycardia persists longer. These findings suggest that firstly sleep influences only partially the variation of these parameters, especially regarding heart rate, and secondly that heart rate is modulated differently from blood pressure throughout the 24 hours (13). An imbalanced autonomic control with preserved parasympathetic activity and a higher background and stimulated sympathetic activity have been shown with autonomic tests in patients with fatal familial insomnia. Several data support a sympathetic overactivity in these patients, such as elevated noradrenaline plasma levels at rest, increasing further under orthostatic stress; exaggerated blood pressure increase in response to physiologic stimuli (postural changes, Valsalva maneuver, isometric handgrip); absent blood pressure response to noradrenaline infusion due to downregulation of adrenoreceptors; abnormal heart rate increase after atropine infusion; and diminished depressor and sedative effects of clonidine (33). A microneurographic study has confirmed sympathetic overactivity in resting wake condition in these patients (43). Another study using heart rate variability (HRV) also found reduced parasympathetic activation in fatal familial insomnia compared to healthy controls and patients with Creutzfeldt-Jakob disease during both wake and sleep stages (37).

Postmortem brain studies in fatal familial insomnia disclosed severe loss of neurons in the thalamus, particularly in the anterior ventral and mediodorsal thalamic nuclei (94). Positron emission tomography studies showed a severe thalamic hypometabolism at the onset of insomnia and dysautonomia, suggesting that damage to the medial thalamus is the cause of these signs and symptoms (35).

The thalamic nuclei involved in fatal familial insomnia belong to the circuits connecting the limbic pre-frontal cortex to the hypothalamus and brainstem. The interruption of these circuits, disconnecting the limbic cortical areas that control instinctive behavior and the areas involved in sleep and autonomic control, results in agrypnia excitata syndrome. This syndrome has also been observed in other diseases in which the thalamolimbic circuits are impaired through different pathophysiological mechanisms: Morvan syndrome, an autoimmune limbic encephalopathy; delirium tremens, the well-known alcohol withdrawal syndrome; and cerebral Whipple disease, an infection caused by Tropheryma whippelii (95; 22).

Recognition of the agrypnia excitata syndrome may be, therefore, useful in clinical practice to uncover a thalamolimbic dysfunction.

[18F]-2-fluoro-1-deoxy-D-glucose positron emission tomography in a patient with fatal familial insomnia

Regional cerebral glucose metabolism was imaged utilizing [18F]-2-fluoro-2-deoxy-d-glucose positron emission tomography in a patient with fatal familial insomnia of 10 months duration. Note the severe thalamic hypometabolism and m...

Congenital central alveolar hypoventilation syndrome

	• Congenital central hypoventilation syndrome is associated with systemic autonomic dysfunction.
	• Patients with central hypoventilation syndrome are at risk of life-threatening cardiac arrhythmias.

Congenital central alveolar hypoventilation syndrome, also known as Ondine curse, is a rare condition characterized by alveolar hypoventilation during sleep and, to a lesser degree, during wakefulness. It usually presents in the newborn period due to a deficient autonomic central control of breathing and a global autonomic dysfunction (140). The term “secondary alveolar hypoventilation” identifies the same syndrome of sleep breathing alteration, but in this form, a structural cause is identified (eg, brainstem tumor, brainstem damage from encephalitis, or neuropathy affecting the respiratory motor nerves).

The disease usually manifests in otherwise healthy infants who do not breathe spontaneously or breathe only shallowly or erratically, or who experience episodes of hypoventilation or apnea, frequently requiring mechanical ventilation immediately after birth. Occasionally, patients may present in the first few months of life with acute life-threatening events (cyanosis, respiratory arrest, hypoxic neurologic damage) or in childhood with signs of end-organ damage from chronic hypoxemia and hypercarbia (cor pulmonale, seizures, or developmental delay). Moreover, late-onset cases (starting in adulthood and usually triggered by general anesthesia or respiratory tract infection) have been described (71).

The pattern of breathing during sleep in patients with congenital central alveolar hypoventilation syndrome is characterized by hypoventilation with decreased tidal volume and respiratory rate, which is more severe during NREM compared to REM sleep. Central apnea may also occur, particularly at sleep onset.

Congenital alveolar central hypoventilation syndrome, despite long being considered a unique disorder of respiratory control, has been recognized as a disorder of autonomic regulation associated with the coexistence of autonomic dysfunctions in other systems involving both the sympathetic and parasympathetic branches. The autonomic control of several functions is impaired, causing abnormalities of pupillary response to light, esophageal dysmotility, swallowing dysfunction, decreased basal body temperature, poor heat tolerance, and sporadic profuse sweating. A study investigating peripheral skin temperature over four 24-hour periods in 25 patients with congenital alveolar central hypoventilation syndrome and 39 similarly aged controls found that in patients, mean peripheral skin temperature was lower overall and at night and peripheral skin temperature variability (interquartile range) was higher at night (124). Further, simultaneous measurement of body core temperature in 23 patients demonstrated that although peripheral skin temperature rhythm remained intact, the phase relationship of peripheral skin temperature to the rhythm of body core temperature was extremely variable (124). This result suggests that peripheral skin temperature lies under its own circadian control, independent of or responding aberrantly to changes in core body temperature. Previous studies also reported data consistent with an impaired cardiovascular autonomic control in congenital alveolar central hypoventilation syndrome, including reduced heart rate variability, blunted cardiovascular response to exercise, orthostatic hypotension, loss of the physiological blood pressure nocturnal decrease, sinus bradycardia, and frequent arrhythmias (sinus pauses), leading to syncope and potentially life-threatening events (146; 84). Prevalence of hypertension in a cohort of children with congenital alveolar central hypoventilation has been found around 33%, and a similar amount presented isolated abnormal nocturnal dipping. Concomitant analysis of heart rate variability showed an association with a relative sympathetic overdrive at night (increased LF/HF ratio with decreased HF) (44). Interestingly, heart rate responses to hypoxia and orthostatic challenges were also found to be related to cognitive outcomes in children and young adults (132). In addition, congenital central alveolar hypoventilation syndrome is frequently associated with Hirschsprung disease (congenital megacolon due to the absence of ganglion cells in the myenteric plexus) as well as other gastrointestinal motility disorders, such as esophageal achalasia (07). Some patients also present with congenital heart disease, disorders of glucose metabolism, neural crest-derived tumors (eg, ganglioblastoma), seizures, and developmental delay (146; 140).

A genetic basis of the disease has been recognized with the discovery of mutations of the paired-like homeobox gene 2B (PHOX2B) on chromosome 4p12 (03), which encodes for a transcription factor that plays a role in the regulation of neural crest cell migration and embryologic development of the autonomic nervous system (67). The selective stimulation of Phox2b-expressing neurons located in the nucleus tractus solitarii, the center that integrates cardiovascular and respiratory afferents, resulted in an excitatory drive to a respiratory central pattern generator and potentiated baseline pulmonary ventilation in mice, also pointing to a role of these neurons in the control of breathing (54). Nearly 90% of patients are heterozygous for PHOX2B mutations causing expansion of the 20-residue polyalanine region of this transcription factor. The remaining 10% are heterozygous for a nonpolyalanine repeat mutation, including missense, nonsense, and frameshift mutations of the PHOX2B gene. Most mutations occur de novo, but 5% to 10% are inherited from a mosaic of typically unaffected parents. In both cases, the inheritance of the PHOX2B mutation is autosomal dominant. The PHOX2B genotype correlates with the severity of the phenotype and has, therefore, not only a diagnostic but also a prognostic role. Certain mutations are in fact associated with worse respiratory involvement as well as higher risk of associated disorders such as fatal arrhythmias (99).

A homozygous frameshift mutation in the gene encoding for the unconventional myosin 1H, a protein involved in intracellular transport and vesicle trafficking, was found to cause a recessive form of central alveolar hypoventilation syndrome with autonomic dysfunction in three kindred of a consanguineous family. The study also demonstrated hypoventilation and blunted response to CO2 in mutant myosin 1H mouse strain, suggesting an important role of this gene in respiratory control (136). Similarly, a recessive form of central alveolar hypoventilation syndrome was described in two siblings from a consanguineous family due to a homozygous frameshift mutation in the LBX1 gene. The mutation suppressed only some functions of the gene, leaving others intact. In particular, the mutation in the mouse model interfered with the development of neurons expressing both Lbx1 and Phox2b located in the retrotrapezoid nucleus, which has a key role in the modulation of the respiratory rhythm (70).

Functional alterations of brain areas involved in autonomic control have been demonstrated in congenital central alveolar hypoventilation syndrome. Macey and coworkers analyzed, through fMRI, signal brain responses to a voluntary Valsalva maneuver in patients with congenital central alveolar hypoventilation syndrome compared to controls (96). Increased signals emerged in controls in the cingulate, right parietal cortex, cerebellar cortex, fastigial nucleus, and basal ganglia whereas anterior cerebellar cortical areas and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in patients. The authors suggested that the delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas might be implicated in the cardiorespiratory integration deficits in congenital central alveolar hypoventilation syndrome. A further study, assessing neural response patterns to Valsalva maneuver in 9 patients with congenital central alveolar hypoventilation syndrome and 25 control subjects demonstrated muted responses across multiple brain areas, particularly in the insulae and ventral cerebellum of patients compared to controls (106).

Overall, data demonstrated that congenital central alveolar hypoventilation syndrome is a disorder of autonomic regulation, causing autonomic dysfunctions in other systems. Central alveolar hypoventilation is, therefore, the most severe manifestation of a generalized autonomic nervous system dysfunction.

Obstructive sleep apnea

	• Obstructive sleep apnea syndrome causes sympathetic overactivity during both sleep and wakefulness.
	• Autonomic dysfunction induced by obstructive sleep apnea is linked to long-term cardiovascular and cerebrovascular complications.

Obstructive sleep apnea is characterized by repetitive episodes of complete (apnea) or partial (hypopnea) upper airway obstruction during sleep, which result in blood oxygen desaturation and often terminate by a brief arousal (02).

The apneic episodes exert acute and chronic consequences on cardiovascular parameters as well. Regarding the acute effects, apnea onset induces heart rate and blood pressure decreases, followed by tachycardia and blood pressure surge once breathing restarts. These changes were first demonstrated by Coccagna and colleagues in 1972 and were confirmed thereafter. Overactivity of the sympathetic nervous system occurring in relation to the apneic episodes has also been demonstrated and is probably due to a hypoxia-induced tonic activation of excitatory chemoreflex afferents, which may increase efferent sympathetic activity to muscle circulation. Furthermore, there is evidence of a depression of spontaneous baroreceptor reflex sensitivity in patients with severe obstructive sleep apnea disorder, which may be involved, together with hypoxia-induced chemoreceptor stimulation, in sympathetic overactivation during sleep (92). In addition, sleep disruption due to the repetitive episodes of obstructive sleep apnea may concur with the increased sympathetic drive. Kim and colleagues found that the arousal index better correlated with the sympathetic parameters of heart rate variability compared to the apnea-hypopnea index (80).

Sympathetic overactivity was demonstrated in patients with obstructive sleep apnea also during wakefulness. In 1994, Cortelli and coworkers demonstrated that patients with normotensive obstructive sleep apnea have higher heart rate and norepinephrine plasma levels at rest during wakefulness and a higher blood pressure response to head-up tilt compared to controls, suggesting diurnal sympathetic overactivity (34). Further, when performing cardiovascular reflex tests, these patients showed significantly lower values of respiratory arrhythmia and Valsalva ratio associated with a greater decrease in heart rate induced by cold face test, indicating a blunting of reflexes dependent on baroreceptor or pulmonary afferents. Subsequent studies evaluating heart rate variability confirmed a sympathetic predominance in obstructive sleep apnea (127). In addition, autonomic indexes seem to correlate to the severity of obstructive sleep apnea. Measures of heart rate variability during wake and sleep were valuable markers of disease severity (119; 149). Heart rate variability has been used as a tool for assessing the effects of treatment with continuous positive airway pressure (CPAP) therapy on the autonomic nervous system. CPAP was able to improve measures of autonomic balance between the sympathetic and parasympathetic nervous system during tasks like standing and engaging in regular breathing patterns, and to consistently improve the sympathovagal balance with prolonged use (143).

A neuroimaging study demonstrated structural changes in the central autonomic network morphology in patients with moderate-to-severe obstructive sleep apnea compared to controls. In particular, left midcingulate and left posterior thalamic thickening was found in participants with moderate-to-severe obstructive sleep apnea, and thickness correlated with muscle sympathetic nerve activity. Left insular thickness was also observed and correlated inversely with oxygen desaturation but was unrelated to sympathetic firing. These observations suggest obstructive sleep apnea-associated cortical structural alterations in regions participating in neural circulatory regulation (137). Another study employing functional MRI demonstrated alterations in areas of the central autonomic network that correlated to baroreflex sensitivity in patients with obstructive sleep apnea, suggesting that central structures play a role in the autonomic dysfunction associated with this condition (89). However, a further study showed normal functional activation of the insula in response to the Valsalva maneuver in patients with obstructive sleep apnea, questioning the role of this particular area in neural circulatory responses (110).

The main consequence of the described alterations of cardiovascular autonomic control in patients with obstructive sleep apnea is an increased risk of developing cardiovascular and cerebrovascular diseases (hypertension, myocardial infarction, arrhythmias, heart failure, and stroke) (148).

Early investigators recognized hypertension as a clinical feature of obstructive sleep apnea, but until recently, the link between sleep apnea and hypertension was uncertain because of the many confounding factors (obesity, age, and alcohol ingestion). However, there is now much epidemiological evidence supporting a direct contribution of sleep apnea to hypertension (60). Blood pressure surges and the degree of blood pressure fluctuations are associated with the amplitude and frequency of oxygen desaturation events and represent the major components of increased nocturnal blood pressure (73). Vice versa, in patients with essential hypertension, the nondipping condition has been found to represent a risk factor for obstructive sleep apnea; screening is advised for this condition (36).

Many hypotheses have been advanced to explain how sleep apnea leads to daytime blood pressure elevation. Important causative factors are the effect of episodic hypoxemia and hypercapnia on chemoreceptors and sympathetic activity, the modification of the cardiovascular system (including fluid balance) in response to marked fluctuations in intrathoracic pressure during obstructive apneas, sleep disruption due to apnea-related arousals and consequent sympathetic activation, and endocrine factors like activation of the renin-angiotensin-aldosterone system. However, increased sympathetic outflow due to increased peripheral chemoreflex sensitivity and reduced baroreflex sensitivity seem to have a prominent role in the etiology of hypertension in patients with obstructive sleep apnea (32; 100). Polysomnographic studies showed a significant association between arousal index and systolic and diastolic blood pressure in patients with obstructive sleep apnea (120).

It has been proposed that alteration of cardiac autonomic modulation and risk of developing cardiovascular diseases, in particular hypertension, are correlated with presence of excessive daytime sleepiness in patients with obstructive sleep apnea. A previous study showed that patients with sleep-related breathing disorder of different disease severity and excessive daytime sleepiness, evaluated through multiple sleep latency test, when compared with patients without excessive daytime sleepiness, had significantly lower baroreflex sensitivity and significantly higher low-to-high frequency power ratio of heart rate variability during the different stages of nocturnal sleep (91). Subsequent studies seemed to confirm a strong association between hypertension and obstructive sleep apnea severity in people with excessive daytime sleepiness (100). On the contrary, a study did not find a correlation of excessive daytime sleepiness with increased sympathetic activity evaluated through heart rate variability during wake before sleep onset and sleep, and with arterial stiffening in male patients with mild-to-moderate obstructive sleep apnea (21). However, in this study, excessive daytime sleepiness was only subjectively evaluated (Epworth sleepiness scale ≥ 10), heart rate variability comparison was not performed in each sleep stage, and patients with severe obstructive sleep apnea were not included. Therefore, despite these controversial results, the assessment of excessive daytime sleepiness in patients with obstructive sleep apnea may have practical clinical implications in the diagnosis or prevention of cardiovascular diseases.

Several cardiac arrhythmias have been associated with obstructive sleep apnea, including atrial fibrillation, sick sinus syndrome, atrial flutter, and ventricular tachycardia (101). Epidemiological data have also consistently demonstrated an independent association between atrial fibrillation and obstructive sleep apnea. The prevalence of obstructive sleep apnea in patients with atrial fibrillation ranges from 21% to 74%. The recurrent episodes of transient oxygen desaturation and intrathoracic pressure changes during the apneas cause repetitive mechanical atrial wall stretch, leading eventually to electrophysiological and structural remodeling of the atrium. Sympathovagal imbalance, as discussed before, may also play a role in arrhythmogenesis (90).

The obstructive sleep apnea-related arrhythmogenesis may also be implicated in sudden cardiac death. A longitudinal study evaluating a population of 10,701 adults who underwent a diagnostic polysomnogram for suspected sleep disordered breathing and were subsequently followed up for an average of 5 years found that incident resuscitated, or fatal sudden cardiac death was best predicted by the presence of obstructive sleep apnea. Furthermore, the magnitude of sudden cardiac death risk was related to severity of obstructive sleep apnea (55). The causal link between sudden cardiac death, which is usually due to a ventricular arrhythmia, and obstructive sleep apnea is still undetermined, but chronic sympathetic overactivity, identified as a risk marker of sudden cardiac death in other clinical conditions, may play an important role.

Short sleep duration was associated with wake-up ischemic stroke in patients with obstructive sleep apnea (72), and severe obstructive sleep apnea was found to be an independent risk factor for a poor functional prognosis in patients with acute ischemic stroke (144). Further studies are needed to elucidate stroke and obstructive sleep apnea comorbid interactions (09).

In conclusion, literature data show that obstructive sleep apnea is associated with an increased sympathetic control of the cardiovascular system and reduced baroreflex sensitivity during both sleep and wakefulness. This autonomic dysfunction is likely to be caused by the sleep disorder itself and to play a prominent role in the development of cardiovascular diseases.

Narcolepsy type 1

	• Narcolepsy type 1 is characterized by sympathetic/parasympathetic activity imbalance during sleep and wakefulness.
	• Autonomic dysfunction with altered heart rate and blood pressure control is likely to represent one of the mechanisms through which narcolepsy type I negatively impacts cardiovascular risk.

Narcolepsy type 1 is a clinical condition characterized by excessive daytime sleepiness accompanied in the classical form by cataplexy, sleep paralysis, and hypnagogic hallucinations (02). Narcolepsy type 1 in humans is associated with loss of hypocretin cells in the lateral and posterior hypothalamus along with reduced level of CSF hypocretin-1. Hypocretins (also called orexins) are neuropeptides involved in the circadian timing of sleep and wakefulness that also play a role in many autonomic functions (64).

Patients with narcolepsy type 1 present with a wide range of symptoms of autonomic dysfunction. One study evaluating autonomic symptoms by means of the SCOPA-Aut questionnaire in 92 patients found that the total score, as well as the scores for each subdomain (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual), were higher in narcoleptic patients than in controls and were associated with altered quality of life (11). Interestingly, they did not correlate to orexin levels nor differ according to treatment status. Indeed, the exact effects of hypocretins on the autonomic nervous system and, in particular, on cardiovascular control are still controversial (20). Work on a mouse model of narcolepsy type 1 showed that arterial pressure alterations during sleep resulted from alterations in sympathetic control of the heart and resistance vessels (01), suggesting possible links between orexin deficiency and the cardiovascular autonomic system.

Studies investigating autonomic control of the cardiovascular system during both sleep and wakefulness in humans have led to conflicting results (23). Grimaldi and colleagues characterized the 24-hour circadian rhythm and the day-, nighttime-, and state-dependent changes of blood pressure and heart rate in drug-free narcoleptic patients compared to controls (62). The study demonstrated the presence of normal 24-hour circadian rhythmicity for blood pressure and heart rate in narcoleptic patients who, however, showed 24-hour mean heart rate values higher than controls and a nighttime non-dipping blood pressure profile with physiological daytime blood pressure values. Systolic blood pressure values were significantly higher during nighttime REM sleep in narcoleptic patients. Furthermore, patients showed increased sleep fragmentation, arousal index, periodic limb movements of sleep, and number of arousals related to periodic limb movements of sleep; however, only an increased number of periodic limb movements of sleep was consistently associated with the blunted nighttime decrease in blood pressure.

Another study using 24-hour ambulatory blood pressure monitoring found a higher percentage of patients with nondipping diastolic blood pressure in a sample of 36 patients with narcolepsy type 1 compared to 42 controls (30% vs. 3%) (38). The diastolic nondipping profile was negatively correlated with the percentage of REM sleep. Daytime values of systolic and diastolic blood pressure were not significantly different in the two groups whereas daytime heart rate values were slightly but not significantly lower in patients with narcolepsy type 1.

A blood pressure nondipping profile suggests a sympathetic-parasympathetic imbalance during sleep in patients with narcolepsy type 1, which may be due to either sympathetic prevalence or parasympathetic withdrawal. However, skin sympathetic activity and muscle sympathetic nerve activity were normal during NREM and REM sleep in 13 patients with narcolepsy type 1, despite showing a nondipping blood pressure profile (42).

Sieminski and Partinen demonstrated that a blood pressure nondipping profile occurs equally in a group of narcoleptic patients compared to a group of patients with insomnia, suggesting that sleep disturbance, rather than an absence of orexin, might cause a reduced blood pressure dipping (129). The same authors subsequently observed that daytime and nocturnal blood pressure did not differ between narcoleptic patients with a complete depletion of orexin and those with a remaining, limited presence of orexin (Sieminski and Partinen 2017). Most patients in this study showed a nondipping blood pressure pattern regardless of group. These results do not support the hypothesis that in patients with narcolepsy type 1, residual orexin levels play a role in the control of nocturnal blood pressure dipping.

By assessing pulse transit time as a marker of arterial blood pressure modulation during sleep, one study found blunted sleep-related changes in arterial blood pressure from wake to sleep in children with narcolepsy type 1 (142). This alteration was associated with lower cerebrospinal fluid hypocretin-1 levels, suggesting that the impaired control of blood pressure may be a direct result of the hypocretin loss.

A blunted heart rate increase associated with periodic limb movements, other leg movements, and arousals during sleep was observed in patients with narcolepsy type 1 compared to controls (39; 135), suggesting a decreased sympathetic tone related to hypocretin-1 deficiency. However, in the latter study, the baseline heart rate values during sleep were significantly elevated in the narcolepsy type 1 group, and the attenuated heart rate increase could be explained by the already elevated basal heart rate values (135). Higher heart rate values throughout sleep states and during wakefulness prior to sleep were confirmed in patients with narcolepsy type 1 compared to controls. These elevated values were independent of sleep stage duration and sleep fragmentation, suggesting a direct effect of hypocretin deficiency. The same study observed a blunted heart rate increase in response to awakenings from NREM sleep in the group with narcolepsy type 1 (141).

Studies investigating autonomic cardiovascular control during wakefulness in these patients also showed conflicting results. One study found lower diurnal resting muscle sympathetic nerve activity associated with lower heart rate and blood pressure values in narcoleptic patients compared to controls, suggesting a decreased sympathetic tone (41). On the contrary, another two studies using heart rate variability found increased sympathetic-parasympathetic balance during wakefulness preceding sleep (51) and an enhanced sympathetic activity at rest (63) in narcoleptic patients. Rocchi and colleagues studied 12 de novo patients with narcolepsy type 1 by means of cardiovascular function tests (tilt test, Valsalva maneuver, deep breathing, handgrip, and cold face) performed under controlled conditions (121). The results of this study suggested that narcolepsy was characterized by sympathetic hyperactivity (higher blood pressure values at rest and during tilt test) and reduced parasympathetic activity (significant heart rate alterations).

Cardiac sympathetic innervation studied by means of 123-meta-iodobenzylguanidine myocardial scintigraphy was not impaired in patients with narcolepsy, favoring the hypothesis that hypocretin does not have a direct effect on cardiac adrenergic nerve activity (12).

Patients with narcolepsy are at increased risk of new onset cardiovascular events. These include stroke, myocardial infarction, cardiac arrest, and heart failure (19). These conditions may share the same pathophysiology, including autonomic dysfunction. Alternatively, clinical features of narcolepsy such as sleep disruption may secondarily impact the cardiovascular system. It is possible that both types of mechanisms occur simultaneously. Indeed, as mentioned above, there is some evidence linking lack of hypocretin to autonomic dysfunction. Other pathways that may be implicated include endothelial dysfunction and myocardial function, which may also be affected by hypocretin deficiency (76). Furthermore, several factors that are known to increase cardiovascular risk directly or by increasing the sympathetic tone (tendency to obesity, tobacco smoking, periodic limb movements during wakefulness and sleep, restless legs syndrome, and obstructive sleep apnea) have an increased rate of occurrence in narcolepsy type 1. The extent to which the combination of these factors increases cardiovascular risk and mortality in these patients has to be determined (20). Given that narcolepsy is a chronic condition and patients are usually young, this increased cardiovascular risk should be always taken into account by treating physicians.

In summary, patients with narcolepsy type 1 show impaired autonomic control of the cardiovascular system characterized by variable imbalance of sympathetic and vagal functions during sleep and wakefulness. The precise link is still undetermined. Further studies evaluating autonomic control during both wakefulness and sleep are necessary in these patients to clarify this issue.

REM sleep behavior disorder

	• Autonomic dysfunction is closely associated with REM sleep behavior disorder.
	• The potential prognostic role of autonomic dysfunction for phenoconversion to Parkinson disease and other alpha-synucleinopathies is not established yet.

REM sleep behavior disorder is a sleep parasomnia characterized by dream-enacting behaviors, often violent and injurious, occurring during REM sleep and associated with loss of the physiological REM muscle atonia (02).

This condition may be either idiopathic or associated with another neurologic disorder (secondary REM sleep behavior disorder), and it is frequently observed in the alpha-synucleinopathy family of neurodegenerative disorders, like Parkinson disease, Lewy body dementia, and multiple system atrophy, which are also associated with autonomic sympathetic failure (orthostatic hypotension, sexual dysfunction, neurogenic bladder and bowel). The onset of REM sleep behavior disorder can precede, by several years, the onset of these diseases, and results from longitudinal studies have shown that most patients with the idiopathic form eventually develop a neurodegenerative disease (74; 126). As a consequence, several studies have tried to disclose signs potentially predictive of a neurodegenerative disease in patients with idiopathic REM sleep behavior disorder by means of clinical, neuropsychological, electrophysiological, and neuroradiological modalities.

An impairment of autonomic functions can be detected in patients with idiopathic REM sleep behavior disorder (28). Mahowald and Schenck first noted the lack of heart rate changes in association with the vigorous behaviors during REM sleep shown by these patients (97). Three subsequent studies reported a blunted heart rate increase associated with different sleep-related movements in patients with idiopathic REM sleep behavior disorder compared to controls and to subjects with restless legs syndrome (50; 47; 134). In addition, the physiologic parasympathetic withdrawal and sympathetic increase observed during REM sleep compared to NREM sleep is lacking in patients with idiopathic REM sleep behavior disorder (85). Patients with idiopathic REM sleep behavior disorder presented an impaired nocturnal blood pressure profile, with reduced amplitude of nocturnal dipping and increased frequency of nondipping status (138).

Studies assessing autonomic function during wakefulness in idiopathic REM sleep behavior disorder also proved autonomic impairment. Rocchi and colleagues investigated autonomic function by means of cardiovascular reflex tests (tilt test, Valsalva maneuver, deep breathing, cold face, and handgrip test) in 14 patients with idiopathic REM sleep behavior disorder, and they found pathological results at the Valsalva maneuver and deep breathing tests compared to healthy controls, suggesting an impairment of both sympathetic and parasympathetic functions (122). Sudomotor function was also tested with Sudoscan and was abnormal in 29% of the patients. Zitser and coworkers found postganglionic sudomotor abnormalities by means of quantitative sudomotor axon reflex test (QSART) in 20% of patients with idiopathic REM sleep behavior disorder (151). Reduced pupillary responses were also noted in idiopathic REM sleep behavior disorder patients (113). A large prospective multicenter study estimated that the prevalence of orthostatic hypotension in idiopathic REM sleep behavior disorder was 27%, of which 77% meets the criteria for neurogenic orthostatic hypotension according to the Δ heart rate/Δ systolic blood pressure (ΔHR/ΔSBP) ratio less than 0.5. Seventy-two percent of patients with orthostatic hypotension also presented supine hypertension (45). Interestingly, there was no difference in patients’ symptoms between those with and without orthostatic hypotension, indicating that in these patients orthostatic hypotension can be frequently asymptomatic and patients may have reduced awareness of symptoms.

Several questionnaire- and scale-based studies confirmed autonomic abnormalities in idiopathic REM sleep behavior disorder. One study found that patients with idiopathic REM sleep behavior disorder compared to controls complained of significantly more autonomic symptoms, including symptoms suggestive of orthostatic hypotension (49). A study characterized dysautonomia in 17 patients with idiopathic REM sleep behavior disorder using the composite autonomic severity score (87). The study found that 94% of patients showed sympathetic adrenergic or parasympathetic cardiovagal deficits with relatively little sudomotor cholinergic dysfunction, which was mild to moderate in most patients.

Central structures of the autonomic nervous system (ie, the central autonomic network) seem to be compromised in idiopathic REM sleep behavior disorder (88). Patients showed reduced grey matter volume in the brainstem, anterior cingulate, and insula and reduced functional connectivity between the brainstem and the cerebellum posterior lobe, temporal lobe, and anterior cingulate compared to controls. The abnormal structure and functional connectivity of these areas of the central autonomic network correlated with autonomic symptoms reported on the SCOPA-Aut questionnaire.

In summary, most studies observed that autonomic dysfunctions do exist in idiopathic REM sleep behavior disorder. However, whether the autonomic dysfunction in idiopathic REM sleep behavior disorder predicts the subsequent development of a neurodegenerative disease has not been definitively established.

Frauscher and colleagues evaluated 15 patients with idiopathic REM sleep behavior disorder and an equal number of patients with Parkinson disease as well as healthy controls; they used cardiovascular autonomic tests and “composite autonomic scoring scale” to demonstrate the presence of an autonomic dysfunction in patients with idiopathic REM sleep behavior disorder of an intermediate degree between controls and patients with Parkinson disease (52). The authors suggested that idiopathic REM sleep behavior disorder could be an early manifestation of an alpha-synucleinopathy.

However, other studies led to different conclusions. A retrospective study showed a reduction of low-frequency component of heart rate variability during wakefulness in patients initially diagnosed with idiopathic REM sleep behavior disorder compared with controls; however, no difference was detected among patients with REM sleep behavior disorder who subsequently did or did not develop a neurodegenerative disease (116). The same authors found that autonomic dysfunction was not worse in patients with Parkinson disease and REM sleep behavior disorder than in patients with idiopathic REM sleep behavior disorder. Further, REM sleep behavior disorder was shown to predict autonomic dysfunction better than the presence of Parkinson disease (114; 117).

These studies suggested that autonomic dysfunction is integrally related to the pathogenesis of REM sleep behavior disorder rather than a preclinical sign of a neurodegenerative disease. A similar conclusion is proposed by Kashihara and colleagues, who demonstrated that cardiac (123)I-metaiodobenzylguanidine uptake is more markedly reduced in patients with idiopathic REM sleep behavior disorder compared to those with Parkinson disease (79). Another prospective study confirmed cardiac denervation in patients with REM sleep behavior disorder; however, it did not find significant differences with reference values for patients with Parkinson disease (81). Similarly, 123-I-metaiodobenzylguanidine myocardial uptake showed progressive reduction but no difference between converters and nonconverters in 12 out of 14 patients with idiopathic REM sleep behavior disorder assessed after 3 years follow-up (48).

In the current largest prospective study of idiopathic REM sleep behavior disorder involving 1280 patients, the conversion rate to a neurodegenerative syndrome (Parkinson disease, dementia with Lewy bodies, or multiple system atrophy) was 6.3% per year, with 73.5% converting after 12-year follow-up (115). Baseline risk factors for subsequent conversion were abnormal quantitative motor testing, motor symptoms (not parkinsonism), abnormal DAT scan, olfactory deficit, mild cognitive impairment, erectile dysfunction, color vision abnormalities, constipation, and age. No marker was specific to a single diagnosis, including autonomic failure for multiple system atrophy. However, formal autonomic testing was not performed in this study. In another large, multicenter prospective study, the combination of constipation and reduced nigroputaminal dopaminergic function were high risk factors for short-term phenoconversion to synucleinopathy (05). McCarter and colleagues assessed the prevalence and predictive value of autonomic dysfunction and evaluated it with standardized autonomic function tests in a cohort of 18 patients with idiopathic REM sleep behavior disorder with clinical follow-up of at least 3 years (103). The authors found a high prevalence (83%) of autonomic dysfunction in patients with idiopathic REM sleep behavior disorder, and they found a more severe baseline cardiovagal impairment was associated with phenoconversion to dementia with Lewy bodies (103).

The association between REM sleep behavior disorder and autonomic dysfunction has also been investigated in other settings. Interestingly, in a large cohort of patients with pure autonomic failure (ie, long standing isolated autonomic failure), earlier onset (but not the sole presence) of REM sleep behavior disorder predicted conversion to a central nervous system synucleinopathy (56). Another study found that patients with multiple system atrophy presenting with REM sleep behavior disorder before disease onset had more frequently autonomic rather than parkinsonian onset, an earlier onset of orthostatic hypotension and urinary dysfunction, and a shorter disease duration (57). REM sleep behavior disorder was associated with dysautonomia but not with motor and cognitive measures in a cohort of patients with early Parkinson disease (40). Therefore, REM sleep behavior disorder seems to be closely connected to autonomic failure and associated with a worse prognosis in synucleinopathies.

In conclusion, patients with idiopathic REM sleep behavior disorder commonly present autonomic dysfunction, particularly in the form of postganglionic, cardiac sympathetic denervation. However, the precise correlation of autonomic dysfunction with REM sleep behavior disorder severity and phenoconversion rate needs still to be clarified (150). A review by Miglis and colleagues discusses autonomic as well as other biomarkers of conversion to alpha-synucleinopathies in idiopathic REM sleep behavior disorder (104).

All these data and the importance of finding early markers of neurodegenerative disease indicate that further systematic prospective autonomic investigations are required in patients with idiopathic REM sleep behavior disorder to better clarify the association between autonomic dysfunction and REM sleep behavior disorder and their predictive role in the early diagnosis of neurodegenerative diseases.

Prognosis and complications

Fatal familial insomnia is uniformly fatal, leading to death from onset of insomnia after either a short (less than 12 months) or a long (12 to 72 months) course. In addition to sleep and autonomic signs and symptoms, somatomotor abnormalities, including gait dysfunctions, appear with variable latency and degree during the disease course, and in later stages of the disease patients become bedridden. Death can then occur from sudden cardiorespiratory failure or from respiratory or systemic infections.

The mortality rate in congenital central alveolar hypoventilation syndrome varies from 8% to 38% among studies and has been reduced with modern techniques for home ventilation.

Obstructive sleep apnea, particularly if untreated, may lead to serious cardiovascular consequences (related to nocturnal hemodynamic alterations) and to excessive daytime sleepiness. Obstructive sleep apnea is, in fact, an important risk factor for hypertension, cardiac arrhythmias, myocardial infarction, congestive cardiac failure, and stroke (148). Moreover, reduction of diurnal vigilance may increase the risk of car or work accidents. Unrecognized obstructive sleep apnea in adult patients undergoing major noncardiac surgery was found to be associated with increased risk of 30-day postoperative cardiovascular complications (26). The heart rate response to an apnea or hypopnea event has been proposed as a useful tool to stratify the risk for cardiovascular disease in patients with obstructive sleep apnea, once again highlighting the role of sympathetic and parasympathetic imbalance in the development of these complications (06). Further prospective studies need to validate these interesting findings.

Patients with narcolepsy type 1 may show a nocturnal non-dipper blood pressure profile, which is known to increase cardiovascular risk in humans. There is evidence that narcolepsy type 1 is associated with arterial hypertension, particularly in elderly patients (107; 83), and with an increased mortality (108). The impact of several factors like obesity, other sleep disorders (sleep-disordered breathing, periodic limb movements, and restless legs syndrome), tobacco smoking, and dysfunction of autonomic cardiovascular control on the cardiovascular risk and mortality of patients with narcolepsy has to be determined.

REM sleep behavior disorder can precede the onset of neurodegenerative diseases by several years, and this is the most important factor for a long-term prognosis.

Clinical vignette

A 45-year-old woman presented to the Sleep Disorders Center complaining of severe motor disorders during sleep. Her husband related that while asleep, she would suddenly start shouting, punching, and kicking as if defending herself from attack. In one of these episodes, the husband was punched in the eye, and his wife would often fall out of bed inflicting cuts and bruises on herself. Neurologic examination was normal as were biochemical and neuroradiological investigations. A diagnosis of idiopathic REM sleep behavior disorder was made, and the patient was given 0.5 mg clonazepam at bedtime, which improved sleep quality and reduced the motor events. One year later, the patient returned to the Sleep Disorders Center because after meals she was overcome by an irresistible urge to sleep associated with severe pain in her neck muscles, which subsided as soon as she went to bed. Postprandial EEG disclosed diffuse slowing in a sitting position that disappeared when supine. Investigation into autonomic control of cardiovascular reflexes revealed severe orthostatic hypotension (-50/-30 mm Hg) with fixed heart rate and absent baroreceptor reflex. A study of arterial pressure circadian rhythm showed an absent physiological pressure fall during sleep (non-dipper) and the patient was prescribed 10 mg midodrine 30 minutes before meals and advised not to go to bed before midnight to avoid worsening the nocturnal arterial hypertension. Two years later she presented resting and postural tremor, plastic-type rigidity mainly in the trunk, and gait ataxia. A diagnosis of probable multiple system atrophy was made.

Biological basis

Etiology and pathogenesis

	• Sleep induces a physiological modulation of cardiovascular and respiratory autonomic functions.
	• Alterations of either sleep or autonomic function have consequences on each other.

Neuronal populations in the pons, basal forebrain, and other subcortical areas, acting mainly through the neurotransmitters norepinephrine, serotonin, and acetylcholine, coordinate the transition from wake to sleep and the subsequent development of different sleep stages. These neuronal populations are reciprocally interconnected with areas of the central nervous system involved in autonomic control owing to the central autonomic network, which through its ascending and descending connections orchestrates the sympathetic and parasympathetic divisions of the autonomic nervous system (18).

As a consequence, sleep induces profound changes in the functions of the autonomic nervous system, and disorders of sleep may cause or be associated with dysfunction of the autonomic nervous system during both sleep and wakefulness.

In this section we describe physiological cardiovascular and ventilator autonomic control during sleep and the suggested abnormalities that lead to autonomic dysfunction in obstructive sleep apnea and congenital central alveolar hypoventilation syndrome.

Physiological NREM sleep is characterized by electrocortical synchronization, reduced muscle tone, and parasympathetic predominance. Sympathetic activity progressively decreases and parasympathetic activity increases from wakefulness to deep NREM sleep associated with a tonic decrease in arterial blood pressure and heart rate (133).

Healthy normotensive persons show a 10% to 20% blood pressure decline during sleep compared to mean daytime values, a phenomenon referred to as “dipping.” A non-dipper blood pressure profile is defined as a blood pressure reduction of less than 10% and is known to increase cardiovascular risk in humans (69).

The combination of lower arterial blood pressure, heart rate, and sympathetic nerve activity during NREM sleep suggests that this state is associated with a downward resetting and increased sensitivity of the baroreceptor reflex, which is the most important mechanism involved in blood pressure control. The arterial baroreceptors, mainly located in the carotid sinuses and aortic arch and innervated by the glossopharyngeal and vagus nerves, respond to changes in carotid or aortic stretch elicited by rises or falls in arterial blood pressure and provide inputs to the nucleus of the solitary tract. Activation of the baroreceptors in response to a blood pressure increase elicits a decrease in sympathetic activity and an increase in parasympathetic control of the heart, causing a decrease in total peripheral resistance and heart rate and a subsequent reduction of venous return and cardiac output. Opposite consequences, tachycardia and vasoconstriction, are evoked by a decrease in arterial blood pressure (18). The slope of the heart rate changes in response to blood pressure changes (baroreflex sensitivity, msec/mmHG) is used to estimate baroreflex function (112). Baroreflex activity is modulated by areas of the central autonomic network whose top-down inputs directed to the nucleus of the solitary tract contribute to blood pressure control. However, the nucleus of the solitary tract also exerts a bottom-up modulatory role by its ascending projections to the upper brain.

The arterial chemoreceptors in the carotid bodies and aortic arch also participate in the regulation of cardiovascular parameters. Hypoxia-induced stimulation of these chemoreceptors may lead to sympathetically mediated vasoconstriction, resulting in blood pressure increase and parasympathetic mediated heart rate decrease.

Reduced baroreflex sensitivity and hyperactive chemoreflex function have been hypothesized as causal mechanisms of sympathetic overactivity and increased risk of cardiovascular diseases observed in obstructive sleep apnea. This combination also suggested that a central remodeling of autonomic cardiovascular control may precede the development of daytime hypertension in obstructive sleep apnea (34; 32). The sympathetic activation, which occurs as an acute effect of obstructive sleep apnea, when repeated over a long period of time in predisposed subjects, may change the afferent regulation of the barosensitive neurons located in the nucleus of the solitary tract. This could attenuate their inhibitory effect on the sympathoexcitatory neurons, which could in turn be responsible for the sustained chronic peripheral sympathetic overactivation and its cardiovascular consequence (32).

REM sleep is characterized by electrocortical desynchronization, muscle atonia, phasic fluctuations of sympathetic and parasympathetic activity, and impairment of baroreflex responses. From NREM to REM sleep, a progressive predominance of sympathetic tone is observed. However, during tonic REM sleep, bradycardia and decreased peripheral resistance occur, resulting in arterial pressure decrease. This decrease in arterial pressure is interrupted by large transient increases in arterial pressure and in heart rate during bursts of REMs and muscle twitches. Variability of these cardiovascular parameters results from phasic inhibition of parasympathetic activity and phasic increases in sympathetic discharge.

A progressive inactivation of voluntary control of ventilation occurs in the transition from wakefulness to sleep; during NREM sleep, ventilation is only automatically driven by chemical feedback related to arterial CO2 and O2 levels. Sleep onset is characterized by oscillations in breathing amplitude, and sporadic central apneas are observed, whereas during steady NREM sleep, breathing becomes progressively regular. In this stage, a reduction in minute ventilation is observed due to a decrease in tidal volume and respiratory frequency. REM sleep is characterized by breathing variability that seems to be of central origin and is characterized by sudden changes in breathing amplitude and frequency concurrently with REM bursts (17).

In congenital central alveolar hypoventilation syndrome, hypoxic and hypercapnic ventilatory responsiveness was found impaired during sleep, suggesting an impairment of both central and peripheral chemoreceptor function. However, it has also been demonstrated that the arousal response to hypercapnia during sleep is normal in these patients, suggesting that chemoreceptors are functionally preserved whereas the abnormality in congenital central alveolar hypoventilation syndrome may be located in areas of the brain involved in integration of chemoreceptor afferent pathways for ventilation (68).

Diagnostic workup

	• Careful history taking and neurologic examination are the first steps.
	• Laboratory investigations (autonomic testing, video polysomnography) are performed according to the clinical hypothesis.

The first diagnostic step should be directed at assessing, by means of history taking and physical examination, the presence of symptoms and signs of an autonomic dysfunction as well as of sleep disturbances in all patients. A careful history taking is required to diagnose an autonomic dysfunction as mild symptoms may be concealed by compensatory mechanisms. Similarly, diagnosis of a sleep disorder starts from a detailed history of sleep habits, sleeps hygiene, and subjective sleep complaints and is improved by bed partner interview.

Examination should also include the measure of blood pressure during supine rest and in response to upright posture to exclude orthostatic hypotension (27).

Laboratory investigations should be directed by the history and physical examination.

For the diagnosis of nocturnal sleep disorders, the gold standard is represented by overnight video-polysomnography, which includes simultaneous recording of EEG, EOG, EMG of specific muscles, ECG, respiratory activity (oronasal flow and thoracic and abdominal effort), and oxygen saturation (by pulse oximetry).

Video-polysomnography needs to be performed in a specialized laboratory with dedicated staff, which are usually available only in main hospitals with sleep units. Therefore, to assess common conditions like sleep-related breathing disorders, obstructive sleep apnea being the most frequent, video-polysomnography is not a practical test. Consequently, alternatives have been developed for at-home assessments of subjects considered to be at risk of obstructive sleep apnea as well as follow-up to evaluate the efficacy of treatment. Home sleep apnea testing is performed by a portable device monitoring oxygen saturation, respiratory effort, heart rate, and body position.

Peripheral arterial tonometry is another valuable technique that is employed by wearable devices (particularly a wristwatch) and has proven to be reliable, practical, and easily accessible for at-home sleep studies. Peripheral arterial tonometry captures arterial pulse waves in the fingers, which reflect the degree of peripheral vascular resistance and heart rate. Peripheral vascular resistance in this part of the body is strictly dependent on the autonomic nervous system, as vascular beds are densely innervated by sympathetic vasoconstrictor efferent fibers. Activation of the sympathetic nervous system (eg, induced by sleep apnea arousal) results in vasoconstriction mediated by alpha-adrenergic receptors (increase in arterial blood pressure) and, therefore, attenuation of the signal detected by the device. Several studies have demonstrated that respiratory indexes calculated using peripheral arterial tonometry-based portable devices have a positive correlation with those calculated from standard polysomnography studies and are, therefore, reliable (145). The wrist-worn peripheral arterial tone signal device (WatchPAT) was proven to be particularly useful as a screening test to exclude moderate-to-severe obstructive sleep apnea and for follow-up (139).

When an impairment of the physiological circadian variation of autonomic control is suspected, 24-hour polygraphic recordings of the sleep-wake cycle associated with monitoring of cardiovascular parameters (blood pressure and heart rate) and body core temperature as an index of hypothalamic suprachiasmatic nucleus function, may serve to monitor the circadian fluctuations of several autonomic parameters (eg, cardiovascular parameters, ventilation, temperature, perspiration) and their changes in relation to different physiologic states (wakefulness and NREM and REM sleep) (14).

Cardiovascular reflex tests (head-up tilt test, Valsalva maneuver, handgrip, deep breathing, and cold face) are routinely used to assess a dysfunction of cardiovascular autonomic control during wakefulness. These tests measure heart rate and blood pressure changes in response to specific maneuvers, disclosing a dysfunction of the parasympathetic and sympathetic branches and baroreflex activity (31; 27).

Blood samples can also be collected to measure plasma catecholamines during the tests or over a 24-hour period, and this may be useful to characterize the feature (eg, overactivity or failure) and the site (eg, preganglionic or postganglionic) of a sympathetic dysfunction (59).

Spectral analysis of heart rate variability is calculated from the interval between two consecutive R-waves of QRS complexes (RR interval) in the ECG trace. The power spectrum of heart rate variability comprises high-frequency components (0.15 to 0.4 Hz), reflecting parasympathetic outflow and breathing activity, low frequency components (0.04 to 0.15 Hz), mediated mainly by sympathetic activity, and very low frequency components (0 to 0.04 Hz) whose physiological correlates are not fully understood. The low frequency/high frequency ratio is widely used as an indicator of sympathetic and parasympathetic outflow balance during both wakefulness and sleep (24).

Skin and muscle sympathetic nerve activity can be recorded directly by inserting a microelectrode through the skin into the peroneal and median nerves (61).

Finally, imaging studies with radioactive tracers may distinguish the central or postganglionic site of the autonomic lesion. For example, cardiac 123-meta-iodobenzylguanidine scintigraphy is used to assess cardiac sympathetic innervation and is impaired in postganglionic sympathetic disorders (109).

Management

• Treatment of obstructive sleep apnea with CPAP seems to favorably affect autonomic dysfunction.

There is no current treatment for fatal familial insomnia, excepting supportive measures and palliative care. One preclinical study suggested a possible effect of doxycycline in restoring motor circadian activity, although it did not affect onset, progression, nor survival (86).

Patients with congenital central alveolar hypoventilation syndrome require lifetime mechanical assisted ventilation during sleep to ensure adequate ventilation and oxygenation and to prevent acute and long-term consequences. A percentage of patients (from 6% to 33%) require ventilatory support during both wakefulness and sleep. Positive pressure ventilators via tracheostomy, bilevel positive airway pressure, negative pressure ventilators, and diaphragm pacing can all be used in these patients. With the increasing knowledge of the expanded phenotypic spectrum of this condition, including cases with mild respiratory symptoms, less invasive methods of respiratory support could be offered to patients. In any case, assessment and regular follow-up at centers with expertise on this condition are warranted, considering also the possible associated autonomic and systemic disorders (140). Annual cardiac Holter monitoring for at least 72 hours to evaluate abrupt sinus pauses is recommended (131). Heart rate variability as a measure of cardiovascular autonomic balance is used to assess response to new treatments for hypercapnia in these patients (128).

Treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) devices leads to a significant improvement of autonomic modulation, enhancing daytime baroreflex sensitivity and reducing daytime sympathetic overactivity (77). A positive effect on the sympathovagal imbalance assessed by means of heart rate variability analysis is also observed after long-term CPAP treatment in patients with moderate to severe obstructive sleep apnea, likely due to the decreased burden of nocturnal hypoxia (111). Heart rate variability-derived measurements have been proposed as useful tools for monitoring the efficacy of CPAP therapy in clinical practice (125). However, residual autonomic function deficits were observed also in patients with chronic CPAP treatment (75). One study suggested that improvement in cardiovascular parameters is more pronounced at night and in patients with hypertension (53).

Furthermore, CPAP induces a reduction in blood pressure values and catecholamine levels (10). Preliminary evidence from uncontrolled interventional studies suggests also that CPAP applications may prevent cardiac arrhythmias; however, randomized studies are still needed to address this issue (123). Other treatment options for obstructive sleep apnea include positional therapy (keep people sleeping on their side), behavioral and lifestyle modifications (weight loss), and oral appliances (60). The effects of these measures on autonomic parameters still need to be explored. Exercise training improved the parameters of heart rate variability and baroreflex sensitivity in patients with obstructive sleep apnea in one study (04).

For the management of REM sleep behavior disorder, refer to the specific MedLink Neurology article on this topic. Diagnosis of cardiovascular autonomic sympathetic dysfunction in idiopathic REM sleep behavior disorder has clinical implications as autonomic symptoms, like syncope due to orthostatic hypotension, can be treated with appropriate medications.

Special considerations

Pregnancy

In patients with congenital central alveolar hypoventilation syndrome, the level of ventilator support may need to be adjusted as pregnancy progresses for the effect of pregnancy on ventilation, most likely secondary to the increased strain on the diaphragm by the elevated abdominal pressure of a gravid uterus (15). In addition, prenatal testing should be offered to pregnant patients with congenital central hypoventilation syndrome to inform delivery decisions and prepare for the provision of advanced neonatal care (98).

Anesthesia

Patients with autonomic dysfunctions (in particular, sympathetic failure) are at increased risk for cardiovascular lability during anesthesia. The most relevant aspects to the care of these patients in the perioperative settings are addressed in a review by Mustafa and colleagues (105).

Available literature concerning the perioperative evaluation, the anesthetic techniques, and the postoperative procedures in patients with congenital central alveolar hypoventilation syndrome has been reviewed. Anesthesiologists need also to be aware of undiagnosed late onset congenital central alveolar hypoventilation syndrome and include this condition in the differential diagnosis of patients with unexplained postoperative respiratory depression (15).

A study demonstrated that narcoleptic patients had similar intraoperative courses as controls, including phase 1 anesthetic recovery. However, narcoleptic patients had a higher rate of emergency response team activations in the 48 hours after post anesthesia care unit discharge, mainly due to hemodynamic instability, which suggests that patients with narcolepsy may be at increased perioperative risk (25).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Giovanna Calandra-Buonaura MD PhD

Dr. Calandra-Buonaura of the University of Bologna has no relevant financial relationships to disclose.
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Francesca Baschieri MD

Dr. Baschieri of the University of Bologna has no relevant financial relationships to disclose.
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Editor

Antonio Culebras MD FAAN FAHA FAASM

Dr. Culebras of SUNY Upstate Medical University at Syracuse has no relevant financial relationships to disclose.
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Former Authors

Carolina Lombardi MD PhD
Pietro Cortelli MD PhD

Patient Profile

Age range of presentation: 2 to 65+ years
Sex preponderance: not applicable
Heredity: Not applicable
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Unspecified sleep disturbance: 780.50
ICD-10: Sleep disorder: G47

Sleep disorder, unspecified: G47.9
OMIM: Fatal familial insomnia: #600072

Congenital central hypoventilation syndrome: #209880

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Autonomic dysfunction in sleep disorders

Associated Disorders

Hirschsprung disease and congenital central alveolar hypoventilation syndrome
Ganglioblastoma and congenital central alveolar hypoventilation syndrome

Differential Diagnosis

brainstem lesions
alpha-synucleinopathies

Also Relevant

Central alveolar hypoventilation
Fatal familial insomnia
Obstructive sleep apnea
Narcolepsy
Rapid eye movement sleep behavior disorder

Clinical Categories

Patient Handouts

Problem sleepiness

Autonomic dysfunction in sleep disorders

Introduction

Overview

Key points

Historical note and terminology

Table 1. Main Effects of the Sympathetic and Parasympathetic Control on the Target Organs

Clinical manifestations

Presentation and course

Table 2. Primary Clinical Manifestations of Autonomic Control Dysfunction

Fatal familial insomnia

Congenital central alveolar hypoventilation syndrome

Obstructive sleep apnea

Narcolepsy type 1

REM sleep behavior disorder

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

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Hypersomnolence

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