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Autonomic Disorders
Systemic Autonomic Disorders
Definition
Autonomic dysfunction, which is an important cause of disability, accompanies many diseases that affect the central or peripheral nervous system. It may manifest as autonomic failure or autonomic hyperactivity, may be generalized or focal, and may have a subacute, chronic progressive, or intermittent temporal profile. The prognosis of autonomic disorders depends on the underlying condition.
Epidemiology
The most common causes of autonomic failure are neurodegenerative disorders and autonomic neuropathies. Multiple system atrophy ( Chapters 378 and 379 ), which is the most common central neurodegenerative disorder associated with severe autonomic failure, has an estimated incidence of 0.6 per 100,000 persons per year and a prevalence of 3 per 100,000 in persons older than age 50 years. Autonomic failure may also occur in the other central neurodegenerative diseases, such as Parkinson disease ( Chapter 378 ) and Lewy body dementia ( Chapter 371 ), associated with deposition of the protein alpha-synuclein.
By comparison, the most common cause of autonomic neuropathy in the developed world is diabetes mellitus ( Chapter 210 ), but clinically important peripheral neurodegenerative disease is also seen with amyloid deposition ( Chapter 174 ) as well as inherited neuropathies ( Chapter 388 ). After 10 years with type 2 diabetes ( Chapter 210 ), autonomic impairment is detected by abnormal heart rate variability in 65% of patients, and orthostatic hypotension is seen in about 25% of patients. The incidence of light chain (AL) amyloidosis ( Chapter 174 ) is approximately 12 cases per million persons per year, with an estimated prevalence of 30,000 to 45,000 cases per million persons; peripheral nerve involvement occurs in 22% of cases. The incidence of variant amyloid transthyretin (ATTR) amyloidosis is estimated at 0.3 cases per million persons per year, with an estimated prevalence of 5.2 cases per million persons. Although rare, an important cause of hereditary autonomic neuropathy is hereditary sensory and autonomic neuropath type III (HSAN-III), also known as familial dysautonomia or Riley-Day syndrome. This autosomal recessive disorder is seen primarily in Ashkenazi Jewish children, with an incidence of 1 in 3700 live births and a carrier frequency of 1 in 32 individuals in this population.
Pathobiology
The three components of the autonomic system are the sympathetic, parasympathetic, and enteric nervous systems. The sympathetic and parasympathetic outputs are mediated by preganglionic neurons located in the spinal cord or brainstem, as well as by neurons that are located in autonomic ganglia and project to the target organs. Preganglionic neurons activate the autonomic ganglion neurons by releasing acetylcholine, which acts via ganglion-type nicotinic acetylcholine receptors. Sympathetic output depends on preganglionic neurons that are located at the T1-L2 segments of the spinal cord and that activate neurons in the paravertebral and prevertebral ganglia, as well as in the adrenal medulla. The sympathetic division is critical for maintenance of arterial blood pressure, regulation of regional blood flow, thermoregulation, the response to exercise, homeostatic challenges, and external stressors. The primary sympathetic neurotransmitter, which is norepinephrine, acts via α1 receptors to elicit vasoconstriction, pupillary dilation, and smooth muscle contraction in the bladder detrusor muscle and vas deferens; β1 receptors to elicit cardiac stimulation (tachycardia and increased stroke volume); and β2 receptors to elicit relaxation of vascular and visceral smooth muscle. The sympathetic output to the sweat glands is mediated by acetylcholine acting via muscarinic M3 receptors.
Parasympathetic output is critical for reflex control of organs via their effects on local ganglia that are close to or within the target organ. Output from the Edinger-Westphal nucleus, mediated by the oculomotor nerve via the ciliary ganglion, controls accommodation and the pupillary light reflex. Outputs from the salivatory nuclear complex—mediated by the facial and glossopharyngeal nerves via the sphenopalatine, submaxillary, submandibular, and otic ganglia—control lacrimation and salivation. The vagus nerve provides the most widespread preganglionic parasympathetic output to local respiratory, cardiac, and enteric ganglia. The dorsal motor nucleus of the vagus controls motility and secretion in the respiratory and gastrointestinal tracts and also contributes to control of the heart. Neurons located in the nucleus ambiguus provide vagal output to the heart (cardiovagal output) that is critical for the beat-to-beat control of the heart rate. Vagal outputs inhibit heart rate and atrioventricular conduction via M2 receptors. The parasympathetic output is also mediated by noncholinergic neurons that trigger smooth muscle relaxation and vasodilation primarily via release of nitric oxide and vasoactive intestinal polypeptide.
The sacral preganglionic nucleus innervates the pelvic organs and promotes bladder detrusor contraction for micturition, rectal contraction for defecation, and vasodilation of erectile tissues. The enteric nervous system mediates local reflexes for peristalsis and secretion, both independently and under sympathetic and parasympathetic modulation. The primary neurotransmitter of most parasympathetic and enteric neurons is acetylcholine, which acts via M3 receptors, which in turn promote smooth muscle contraction and glandular secretion.
The two main influences controlling sympathetic and parasympathetic output are reflexes triggered by visceral afferent nerves and the descending modulatory influence from the hypothalamus and brainstem. The baroreceptor reflex (baroreflex) is a critical feedback mechanism for buffering changes in arterial pressure. Inputs from the carotid sinus and baroreceptors in the aortic arch, activated by an increase in pulse pressure, reach the nucleus of the solitary tract, which triggers two responses that reduce blood pressure: activation of vagal output to the heart, thereby leading to decrease of the heart rate; and inhibition of sympathetic output to splanchnic and muscle blood vessels leading to a decrease of total peripheral resistance. Upon standing, unloading of the baroreceptors triggers sympathetically mediated vasoconstriction that limits venous pooling in the abdomen and lower limbs. Failure of this efferent baroreflex sympathetic vasoconstrictor response results in neurogenic orthostatic hypotension ( Chapter 49 ). The primary causes are lesions that affect sympathoexcitatory neurons in the rostral ventrolateral medulla, preganglionic sympathetic neurons, and/or noradrenergic ganglion neurons or their axons, and disorders that affect norepinephrine synthesis (e.g., dopamine-β-hydroxylase deficiency) or α1 receptor blockade.
The sympathetic output to the skin is critical for thermoregulatory sweating in response to heat and vasoconstriction in response to cold. Lesions that affect the descending pathway from the hypothalamus to the intermediolateral cell column, cholinergic sympathetic neurons or their axons, or that cause muscarinic receptor blockade impair sweating, thereby leading to anhidrosis and heat intolerance.
Cranial parasympathetic failure manifests with an impaired pupillary response to light as well as impaired lacrimation and salivation. Causes include involvement of individual cranial nerves, parasympathetic ganglion neurons, or muscarinic receptor blockade.
The vagus nerve is frequently affected in length-dependent neuropathies. Vagal impairment primarily affects upper gastrointestinal motility and beat-to-beat control of heart rate. The sacral preganglionic nucleus, which promotes contraction of the bladder detrusor or rectal sphincters, participates in reciprocal inhibitory interactions with the Onuf nucleus that is located at the S1-S3 levels and that innervate the external sphincter and pelvic floor. These interactions, which are controlled by descending inputs from the pons, allow coordination of bladder or rectal contraction and external sphincter relaxation. A neurogenic bladder ( Chapter 115 ) can manifest with detrusor overactivity, detrusor-sphincter dyssynergia, or detrusor activity with urinary retention, depending on the level of the lesion.
Motility in the gut involves peristaltic reflexes that are mediated by the enteric nervous system under the excitatory parasympathetic and inhibitory sympathetic modulation. Disorders affecting enteric ganglia or their extrinsic control primarily result in constipation ( Chapter 118 ) but are occasionally associated with diarrhea ( Chapter 126 ) and fecal incontinence ( Chapter 131 ).
Pathogenesis
Autonomic disorders, which can affect the sympathetic, parasympathetic, or enteric nervous systems, either in isolation or in various combinations, can be classified on the basis of their localization and underlying pathologic substrate ( Table 386-1 ). The main causes of autonomic disorders include neurodegenerative synucleinopathies, autonomic ganglionopathies, small fiber peripheral neuropathies, and focal lesions.
TABLE 386-1
CLASSIFICATION OF AUTONOMIC DISORDERS
| CENTRAL NERVOUS SYSTEM DISORDERS |
|
| GANGLIONOPATHIES |
|
| PERIPHERAL NEUROPATHIES |
|
| OUTPUT-SELECTIVE DISORDERS |
|
| ORTHOSTATIC INTOLERANCE WITHOUT AUTONOMIC FAILURE |
|
Neurodegenerative synucleinopathies that may manifest with prominent progressive autonomic failure include multiple system atrophy, Parkinson disease ( Chapter 378 ), and dementia with Lewy bodies ( Chapter 371 ). These conditions are characterized by the accumulation of abnormally misfolded α-synuclein aggregates that propagate in a prion-like fashion between neighboring cells, thereby leading to progressive disease in the central and peripheral nervous systems.
A second major group of disorders associated with generalized autonomic failure are the autoimmune ganglionopathies. Damage to the autonomic ganglia, which are a major target of autoimmune disorders, produces subacute, generalized autonomic failure. The prototypical example is autoimmune autonomic ganglionopathy, which is caused by antibodies directed against ganglion-type nicotinic acetylcholine receptors and affects transmission at sympathetic, parasympathetic, and enteric ganglia.
The third major group of disorders associated with autonomic failure are small fiber neuropathies ( Chapter 388 ), which affect unmyelinated and small myelinated axons from nociceptors as well as autonomic ganglionic neurons. Autonomic impairment is commonly associated with neuropathic pain and loss of sensation to pain and temperature. Some of these autonomic neuropathies are hereditary, such as hereditary transthyretin-related amyloidosis (hATTR) polyneuropathy (formerly known as familial amyloid polyneuropathy), which is due to mutations of the transthyretin ( TTR ) gene ( Chapter 174 ). Less frequent examples are hereditary sensory and autonomic neuropathies (HSANs), such as HSAN type III (familial dysautonomia) associated with mutations of the ELP1/IKBKAP gene; sodium channelopathies such as those associated with variants in the genes encoding sodium channels Na V 1.7 ( SCN9A ); and Fabry disease associated with mutations of the GLA gene that encodes α-galactosidase ( Chapter 192 ). Focal disorders affecting the central or peripheral nervous system may produce local autonomic manifestations.
Clinical Manifestations
The classical clinical manifestations of autonomic disorders are related to autonomic failure, but other types of autonomic dysfunction may dominate the clinical picture.
Autonomic Failure
The most disabling manifestation of autonomic failure is orthostatic hypotension, defined as a sustained reduction in systolic blood pressure of at least 20 mm Hg or a reduction in diastolic blood pressure of at least 10 mm Hg, usually within the first 3 minutes of standing or a head-up tilt on a tilt table. Orthostatic hypotension indicates volume depletion, impaired peripheral vasoconstriction, or both. Symptoms reflect hypoperfusion of the brain (lightheadedness, cognitive slowing, syncope), retina (blurry or dimmed vision), upper body muscles (“coat hanger pain”), lungs (dyspnea owing to apical hypoperfusion), and, rarely, the heart (angina). These symptoms are typically more severe in the morning and worsen during exercise, after meals (postprandial hypotension) due to splanchnic vasodilation, upon exposure to heat (owing to skin vasodilation), and with prolonged bed rest that results in physical deconditioning. Patients with cognitive impairment may not accurately identify symptoms of organ hypoperfusion. Supine hypertension, defined as systolic blood pressure 140 mm Hg or higher and/or diastolic blood pressure 90 mm Hg or higher, measured after at least 5 minutes of rest in the supine position, occurs in about 50% of patients with neurogenic orthostatic hypotension ( Chapter 64 ). Supine hypertension promotes overnight natriuresis, thereby causing intravascular volume depletion that predisposes to symptomatic orthostasis in the morning.
A second major manifestation of sympathetic failure is widespread anhidrosis, which produces heat intolerance that manifests with lightheadedness, fatigue, and facial flushing upon exposure to a hot environment. Anhidrosis in the feet and hands occurs in small fiber peripheral neuropathies, whereas patchy, non-length-dependent anhidrosis in the trunk and limbs occurs in autonomic ganglionopathies. Focal or regional anhidrosis is associated with compensatory hyperhidrosis, which occurs either adjacent or distant to areas of anhidrosis and leads patients to seek medical attention.
Cranial parasympathetic failure manifests as intolerance to light, dry eyes (xerophthalmia), and dry mouth (xerostomia) ( Chapter 393 ). Upper gastrointestinal dysmotility ( Chapter 122 ) manifests with dysphagia and delayed gastric emptying, thereby producing early satiety, anorexia, nausea, bloating, belching, postprandial vomiting, and pain ( Chapter 122 ). Lower gastrointestinal dysmotility usually manifests with constipation and impaired defecation, but it also can occasionally cause diarrhea. Detrusor overactivity produces urinary urgency with or without incontinence, urinary frequency, and nocturia ( Chapter 115 ). Reduced detrusor activity leads to incomplete bladder emptying, increased postvoid residual, and eventually urinary retention and overflow incontinence.
Orthostatic Intolerance without Autonomic Failure
A frequent cause of orthostatic intolerance is postural tachycardia syndrome (POTS; Chapter 49 ), which is a heterogeneous condition that is defined by a sustained heart rate increment of more than 30 beats per minute within 10 minutes of standing or head-up tilt, associated with symptoms of cerebral hypoperfusion (e.g., lightheadedness) and sympathetic activation (e.g., palpitations and chest pressure). The standing heart rate is typically greater than 120 beats per minute. Some patients have evidence of a mild autonomic neuropathy affecting the lower limbs. Other mechanisms include hypovolemia, venous pooling, cardiovascular deconditioning, and hyperadrenergic states, which may occur in combination.
Neurally mediated (reflex) syncope ( Chapter 49 ) can be triggered by orthostatic stress as well as by visceral stimuli (e.g., deglutition, micturition, or defecation), cough, pain, and emotional states. It may be preceded by manifestations of sympathetic hyperactivity, such as pallor and diaphoresis. Rarely it may be due to carotid sinus hypersensitivity or a manifestation of glossopharyngeal neuralgia ( Chapter 367 ).
Afferent Baroreflex Failure
Afferent baroreflex failure manifests with wide fluctuations of arterial pressure ( Chapter 64 ). The main causes are prior neck radiation or bilateral neck surgery affecting the carotid sinus, familial dysautonomia (HSAN-III), Guillain-Barré syndrome ( Chapter 388 ), and medullary lesions. Baroreflex failure can result in acute hypertensive crisis immediately following a lesion, but it most commonly manifests with fluctuating hypertension that may develop several months or years after surgical or radiation injury. The hypertensive surges are typically associated with tachycardia, diaphoresis, severe headache, and anxiety, thereby resembling a pheochromocytoma ( Chapter 209 ). Patients may experience hypotension during sedation and sleep, or they may experience orthostatic hypotension in the setting of volume depletion or treatment with vasodilators or sympatholytic drugs. Less frequently, patients may have episodes of hypotension and bradycardia or episodes of orthostatic tachycardia.
Autonomic Hyperactivity
Autonomic hyperactivity, which is a life-threatening manifestation of some neurologic, iatrogenic, and toxic disorders, typically manifests with excessive sympathetic output that leads to tachycardia, hypertension, diaphoresis, piloerection, and pupillary dilatation. Sympathoadrenal hyperactivity may lead to intracerebral hemorrhage ( Chapter 377 ), hypertensive encephalopathy ( Chapter 376 ), posterior reversible encephalopathy syndrome ( Chapter 392 ), takotsubo cardiomyopathy ( Chapter 47 ), pulmonary edema ( Chapter 45 ), and supraventricular or ventricular arrhythmias ( Chapters 50 , 51 , 52 , and 53 ). Major causes include traumatic brain injury ( Chapter 368 ), subarachnoid hemorrhage ( Chapter 377 ), status epilepticus ( Chapter 372 ), autoimmune encephalitis ( Chapter 383 ), autonomic dysreflexia after spinal cord injury ( Chapter 368 ), Guillain-Barré syndrome ( Chapter 388 ), and severe emotional stress ( Chapter 362 ). In some conditions, such as severe traumatic head injury ( Chapter 368 ), tetanus ( Chapter 271 ), malignant hyperthermia ( Chapter 400 ), neuroleptic malignant syndrome ( Chapter 402 ), and serotonin syndrome ( Chapter 213 ), sympathetic hyperactivity is associated with hyperthermia, muscle rigidity, and myoclonus. In isolation, excessive parasympathetic activity is rare, except when temporal lobe seizures cause bradycardia, heart block, or asystole.
Sweating Disorders
Sweating disorders (sudomotor dysfunction) may be the sole manifestation of autonomic disorder. Essential or primary generalized hyperhidrosis is typically most pronounced over the face, neck, and upper trunk. Secondary generalized hyperhidrosis is often associated with drugs or systemic illness. Primary focal hyperhidrosis affects palms, soles, axilla, and sometimes the craniofacial region; it may be exacerbated by anxiety, physical exertion, or heat exposure. Anhidrosis, which refers to the absence of sweating, may occur in central or peripheral autonomic disorders or as a side effect of drugs, most commonly anticholinergic agents. Sympathetic vasomotor and sudomotor dysfunction, which are associated with neuropathic pain, hypesthesia, and allodynia affecting one limb, is the typical manifestation of chronic regional pain syndrome ( Chapter 388 ).
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