Embryologic Development

The ANS has its embryonic origins in the multipotential neural crest cells [Hamill and LaGamma, 2002]. The effector components of the ANS develop in the basal plate of the spinal cord and in the neural crest. By the 3rd week of human gestation, the neural plate begins to fuse and the neural crest cells start to migrate. These migrating cells eventually evolve into sensory and autonomic ganglia, as well as the adrenal chromaffin cells. The primitive sympathetic ganglia, in the thoracolumbar portion of the spinal cord, are formed from neural crest cells from the sixth somite to the posterior end of the neural crest and are recognizable by the 5th week of gestation. Preganglionic parasympathetic fibers arise from neural crest cells in the diencephalon and cranial part of the mesencephalon and rhombencephalon to form cranial nerves, and from neural crest cells in the second to fourth sacral segments to provide the parasympathetic supply to the pelvic viscera. The migrating neural crest cells also contribute to the formation of the enteric nervous system. After colonizing the gut, neural crest-derived cells within the gut wall then differentiate into glial cells plus many different types of neurons [Anderson et al., 2006]. Pupils, salivary glands, heart, gastrointestinal tract, and lungs become innervated from the 5th–7th week. In the 10th week, cardiac conducting fibers appear. Diseases due to defects in the neural crest induction, formation, or migration are referred to as neurocristopathies, and genes that cause some of these disorders, like Hirschsprung’s disease, have been cloned in mice models [Shahar and Shinawi, 2003].

Various factors promote normal progression from the embryonic to the mature autonomic and sensory nervous systems [Edlund and Jessell, 1999; Goridis and Brunet, 1999]. The process of differentiation is incumbent upon exposure of migrating neural crest cells to growth factors released by structures along the migratory route and then within the target tissue. Eventually, specificity will be determined by a neuronal cell’s ability to produce specific neurotransmitters. Several key transcription factors have been identified that play critical roles in the development of the ANS, such as the MASH1 and PHOX genes, which are necessary for differentiation of uncommitted neural crest cells to the developing ANS [Sommer et al., 1995; Tiveron et al., 1996]. Another important regulator of development and survival is nerve growth factor (NGF) [Levi-Montalcini, 1972; Thoenen and Barde, 1980]. In the embryonic neuron, NGF binding promotes migration from the neural crest and enhances maturation through neurite outgrowth. In the mature neuron, dependence on NGF decreases but it continues to enhance neurotransmitter synthesis [Thoenen and Barde, 1980].

The Peripheral Autonomic Nervous System

The peripheral ANS is a visceral and largely involuntary motor/effector (efferent) system. Its subdivisions can be defined by their anatomical locations or their function, as mediated by neurotransmitters. Traditionally, the ANS has been divided into sympathetic (thoracolumbar) and parasympathetic (craniosacral) divisions [Pick, 1970]. In addition, there is an important enteric division.

Sympathetic outflow emanates from major nuclei in the hypothalamus, midbrain, and brainstem, and descends through the cervical spinal cord, where axons synapse in the intermediolateral cell mass. From the thoracic and upper lumbar spinal segments, myelinated axons emerge in white rami and synapse in paravertebral ganglia, which are some distance from target organs. Postganglionic fibers, which are unmyelinated, rejoin the mixed nerve through the gray rami and innervate target organs, except for the adrenal medulla, which has only a preganglionic supply (see Figure 98-1). Parasympathetic outflow consists of cranial and sacral efferents. Cranial efferents accompany cranial nerves III, VII, IX, and X, and supply the eye, lacrimal and salivary glands, heart and lungs, and gastrointestinal tract, down to the level of the colon. The sacral outflow supplies the urinary tract and bladder, the large bowel, and the reproductive system. Most parasympathetic ganglia are close to target organs.

Although the traditional concept is that the sympathetic and parasympathetic systems are antagonistic, this is not always the case, as indicated in Table 98-1. Thus, when the sympathetic system is stimulated, a host of receptor systems are activated, including dilatation of the pupil, increase in glandular secretions, bronchodilatation, increase in heart rate and force of contraction, decrease in gastrointestinal tract motility, decrease in function of the reproductive organs, and mobilization of energy substrates. The parasympathetic system tends to have more focal responses, but some effects may be quite broad, particularly with the wide-ranging innervation of the vagus nerve. However, the parasympathetic system appears to have less influence on exocrine and endocrine function.

Table 98-1 Autonomic Nervous System Functions

(Adapted from Axelrod FB et al. Pediatric autonomic disorders. State of the art. Pediatrics 2006;118:309.)

The Central Autonomic Nervous System

The peripheral ANS can operate independently but, to some extent, it is regulated and integrated by the CAN, whose circuitry ranges from the forebrain to the brainstem (Table 98-2) [Loewy, 1990]. The CAN maintains integral relationships with visceral sensory neurons via afferent input, primarily from cranial nerve X (vagus nerve), which is 80 percent afferent, transmitting visceral sensory information from the larynx, esophagus, trachea, and abdominal and thoracic viscera, as well as the stretch receptors of the aortic arch and chemoreceptors of the aortic bodies. This information is relayed through the nucleus tractus solitarius (NTS) to the major cerebral centers concerned with autonomic regulation, which include the amygdala, hypothalamus, midbrain, and forebrain [Loewy, 1990].

Table 98-2 Central Autonomic Network: Anatomy and Function

CAN, central autonomic network.

(Adapted from Axelrod FB et al. Pediatric autonomic disorders. State of the art. Pediatrics 2006;118:309.)

Disorders in the forebrain circuits, such as ischemia secondary to blood flow disturbance or seizures, can cause cardiac arrhythmia [Hilz et al., 2002]. Within this circuitry, the NTS in the medulla oblongata, which receives input from the vagus and glossopharyngeal nerves, functions as a major relay station, allowing continuous feedback and integration. The hypothalamic area appears to have major influences on thermoregulation and sleep–wake cycling. Thus, the CAN serves many critical functions and affects visceromotor and neuroendocrine function, as well as motor and pain modulation. It aids in reflex adjustments of autonomic responses, and integrates autonomic, neuroendocrine, and behavioral responses that, in turn, maintain homeostasis, emotional expression, and response to stress [Benarroch and Chang, 1993; Critchley et al., 2001].

Neurotransmitters

The peripheral ANS provides physiologic responses via multiple neurotransmitters and a chemical coding system of autonomic neurons. The neurotransmitters, which include amino acids, peptides, and monoamines, act by relaying, amplifying, and modulating signals between two neurons, or a neuron and another cell, such as the smooth muscle cell of blood vessel. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse (Figure 98-2). During the last two decades, it has become clear that, within a single neuron, multiple transmitter systems coexist and that, within a given ganglion, the variety and pattern of neurotransmitters is extensive. In turn, multiple organ systems then respond to the neurotransmitters released via various receptor systems.

Fig. 98-2 Schema of pathways in the formation, release, and metabolism of norepinephrine from sympathetic nerve terminals.

Tyrosine is converted into dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH). Dopa is converted into dopamine (DA) by l-aromatic amino acid decarboxylase (AADC). DA is mobilized into vesicles through vesicular monoamine transporter (VMAT), where subsequently it is hydroxylated by dopamine β-hydroxylase (DβH) to form norepinephrine (NE). Nerve impulses release both DβH and NE into the synaptic cleft by exocytosis. The majority of released NE is removed from the synaptic cleft through reuptake into the presynaptic neuron by the norepinephrine transporter (NET). The remaining NE diffuses away from the synapse and may be taken into other cells by extraneuronal monoamine transporter (EMT). Catechol-O-methyltransferase (COMT) is an extraneuronal enzyme that catalyzes the methylation of NE to normetanephrine. NE taken into the presynaptic neuron is either repackaged into vesicles or oxidized by monoamine oxidase (MAO) to dihydroxyphenylglycol (DHPG).

(Adapted from Vincent S, Robertson D. The broader view: catecholamine abnormalities. Clin Auton Res 2002:1;44.)

For both the sympathetic and parasympathetic systems, the preganglionic innervation is largely cholinergic, with terminals releasing acetylcholine (ACh) at the ganglion synapses. For the sympathetic system, norepinephrine (NE) is the major neurotransmitter, although sympathetic cholinergic fibers (with ACh as the transmitter) supply sweat glands. Other postganglionic neurotransmitters include substance P, dopamine (DA), neuropeptide Y, and vasoactive intestinal polypeptide. Some of these neurotransmitters are co-secreted, such as vasoactive intestinal polypeptide with ACh, and neuropeptide Y with NE, which explains the complexity of attempts to block completely the effects of parasympathetic or sympathetic stimulation with single agents.

Under normal circumstances, the concentration of NE in a noradrenergic synapse is determined by the level of sympathetic activity. A steady state is maintained as a result of a careful balance among catecholamine synthesis, storage, release, and reuptake (see Fiugre 98-2) [Vincent and Robertson, 2002]. DA is the first catecholamine to be synthesized, with NE and epinephrine, in turn, being derived from further modifications of DA. Catecholamine synthesis also requires important co-factors; the enzyme dopamine β-hydroxylase (DβH) requires copper as a co-factor, and DOPA decarboxylase requires pyridoxal-phosphate. Approximately 70–90 percent of released NE is removed from the synaptic cleft through reuptake into the presynaptic neuron by the NE transporter. The remaining 10–30 percent is subject to extraneuronal uptake or spills over into the circulation [Eisenhofer et al., 2004].

The catecholamines also are vital neurotransmitters in the CAN, where they mediate such functions as attention, arousal, learning, memory, and mood. Dopamine is produced largely in neuronal cell bodies in two areas of the brainstem, the substantia nigra and the ventral tegmental area. Neurons containing NE and epinephrine also reside within several brainstem nuclei, including the locus ceruleus [Vincent and Robertson, 2002]. These efferent sympathetic neuronal pathways control autonomic reflexes at the level of the brainstem and spinal cord. They regulate postganglionic sympathetic synapses in the peripheral nervous system.

Genetic errors involved in synthesis, transport, storage, or metabolism of the neurotransmitters can result in a variety of autonomic disorders, such as DβH deficiency, in which lack of this essential enzyme results in inability to convert DA to NE, leading to symptoms consistent with sympathetic insufficiency [Robertson et al., 1986].

Vasovagal Syncope

The most frequent noncardiac cause of unexplained transient loss of consciousness, or faint, is vasovagal syncope. It also is known as neurally mediated syncope and neurocardiogenic syncope, common or emotional fainting, or reflex syncope. During vasovagal syncope, vasodilatation and bradycardia occur simultaneously (Figure 98-3). The bradycardia is due to increased parasympathetic (vagal) outflow to the sinus node of the heart. The decrease in blood pressure is due to vasodilatation but the mechanism is not clear. Both reduction in sympathetic vasoconstrictor traffic (i.e., “passive” vasodilatation) and activation of a vasodilator system (i.e.,“active” vasodilatation) have been postulated [Kaufmann and Hainsworth, 2001]. Among the various postulated causes for active vasodilatation is activation of β₂-adrenergic receptors secondary to epinephrine release from the adrenal medulla [Glover et al., 1962], and increased nitric oxide, a powerful vasodilator released by endothelial and other cells [Kaufmann et al., 1993].

Fig. 98-3 Blood pressure and heart rate with continuous recording in a patient with vasovagal syncope.

Both blood pressure (purple shading) and heart rate (green line) decrease after provocative stimulus (venipuncture).

(From Mathias CJ. Orthostatic hypotension and orthostatic intolerance. In: De Groot LJ, Jameson JL, eds. Endocrinology, 5th edn. Philadelphia: Elsevier, 2006:2613.)

Due to insufficient cerebral perfusion, loss of consciousness and postural tone ensue, and the person falls. While on the floor, perfusion to the brain is restored and consciousness is quickly regained. Vasovagal syncopal episodes tend to take place during emotional stress (especially in a warm environment), after an injurious, shocking accident, and during pain. Mild blood loss, poor physical condition, prolonged bed rest, anemia, fever, and fasting are other factors that increase the possibility of syncope in susceptible individuals. The investigation of vasovagal syncope includes tilt-table testing, often with a provocative stimulus, which can be actual or sham venipuncture. Use of additional physiologic and pharmacologic stimuli to induce a syncope, such as lower-body negative pressure or drugs like isoprenaline and adenosine, can produce false-positives.

In general, vasovagal syncope usually is a benign condition and can be induced in anyone, provided the stress is sufficiently great, although thresholds for the response vary. For the majority of individuals, it requires no treatment other than education of the individual and family regarding potential triggers.

Orthostatic Hypotension

Orthostatic hypotension, also called postural hypotension, is a temporary lowering of blood pressure (hypotension), usually due to standing up suddenly (orthostatic). The change in position causes a temporary reduction in blood flow and oxygen to the brain. When an individual stands up, gravity promotes the pooling of blood in the lower extremities, which decreases venous return of blood circulating back to the heart. Normally, cardiac and carotid sinus baroreceptors sense the decrease in blood volume and initiate increased heart rate and peripheral vasoconstriction. The latter increases resistance to blood flow and increases blood pressure. The underlying pathophysiology in individuals with orthostatic hypotension is an impaired efferent sympathetic signal to the arterioles, a failure to release norepinephrine appropriately upon standing, and consequent vasoconstrictive insufficiency resulting in blood pooling in the lower extremities, with subsequent decreased venous return to the heart and brain [Freeman, 2003]. Thus, orthostatic hypotension also is a common feature of a number of central autonomic neurodegenerative disorders, such as multiple system atrophy and Parkinson’s disease, and peripheral autonomic disorders, such as the autonomic peripheral neuropathies, in which there are decreased peripheral noradrenergic neurons or enzyme deficiencies resulting in low levels of NE – for example, in familial dysautonomia and dopamine β-hydroxylase deficiency, respectively. Furthermore, when blood volume is lowered by dehydration or shifted by food ingestion, orthostatic hypotension can be unmasked in physiologically intact individuals, especially older people.

Orthostatic hypotension can be confirmed by measuring blood pressures and heart rate in supine and upright positions. Orthostatic hypotension is defined as a sustained drop in blood pressure of greater than 20 mmHg systolic or 10 mmHg diastolic within 3 minutes of being upright, associated with symptoms. The heart rate response to changes in blood pressure is minimal, although there may be a mild compensatory increase, i.e., below 30 beats per minute. (Figure 98-4). Presyncopal symptoms can appear, and include dizziness, lightheadedness, headache, and tunnel vision. Occasionally, individuals will faint and have syncope. The symptoms typically improve on lying down.

Fig. 98-4 Blood pressure and heart rate before, during, and after head-up tilt in a normal subject and in a patient with orthostatic hypotension.

A, In the normal subject, there is no fall in blood pressure (purple shading) during head-up tilt. B, In a subject with orthostatic hypotension, however, blood pressure falls promptly. The green line represents heart rate.

(From Mathias CJ. Orthostatic hypotension and orthostatic intolerance. In: De Groot LJ, Jameson JL, eds. Endocrinology, 5th edn. Philadelphia: Elsevier, 2006:2613.)

In a physiologically intact individual with no underlying condition, no medical treatment usually is needed for orthostatic hypotension. The most important treatments are assuring adequate fluids and avoiding potential triggers, such as prolonged sitting, quiet standing, warm environments, or vasodilating medications. Other measures that have been found helpful are use of postural maneuvers and physical therapy and exercise [van Lieshout et al., 1992]. When there is a coexisting underlying medical condition, then the orthostatic hypotension can be very debilitating and these supportive measures may not suffice [Freeman, 2003]. In such cases, various medications may be used, i.e., medications that increase blood volume (fludrocortisone, erythropoietin), medications that interfere with the release or action of epinephrine and NE (beta blockers, angiotensin-converting enzyme inhibitors), and medications that improve vasoconstriction (midodrine).

Orthostatic Intolerance/Postural Tachycardia Syndrome

Orthostatic intolerance (OI) is considered as a type of autonomic dysfunction that occurs as part of many autonomic disorders. As upright heart rate usually is increased greatly, the term postural tachycardia syndrome (POTS) also is used [Low et al., 2001].

Characteristically, the symptoms occur on standing and during mild exertion, and frequently there are complaints of lightheadedness, palpitations, and tremulousness. There also may be other symptoms such as visual changes, poor concentration, tiredness and weakness, and, occasionally, syncope.

Investigations demonstrate that, during postural challenge, the blood pressure does not fall, but the heart rate increases by more than 30 beats per minute or rises above 120 beats per minute (Figure 98-5). The supine heart rate usually is normal or slightly raised. Additional findings include a standing plasma NE level of at least 600 pg/mL, and blood volume usually is reduced. In the hyperadrenergic subgroup of OI patients, plasma renin activity and aldosterone are attenuated.

Fig. 98-5 Blood pressure and heart rate measured continuously before, during and after 60-degree head-up tilt.

Blood pressure is shown as purple shading and heart rate as a green line. A, In a normal subject. B, In a subject with orthostatic hypotension due to pure autonomic failure (PAF). C, In a subject with orthostatic intolerance (OI) or postural tachycardia syndrome (POTS).

(From Mathias CJ. To stand on one’s own legs. Clin Med 2002;2:237.)

The etiology of OI is unknown. It has been observed predominantly in young postpubertal females (female to male ratio at least 4:1) and the onset often is predated by a recent viral infection. Further supporting the hypothesis that OI is an immunologically mediated phenomenon is the fact that it often is a prominent feature of other secondary autonomic disorders that are believed to have an autoimmune etiology, such as idiopathic autonomic neuropathy and chronic fatigue syndrome. Increased propensity to venous pooling [Streeten et al., 1998] and a strong association with the joint hypermobility syndrome have been reported [Gazit et al., 2003].

The majority of patients with OI have a relatively mild disorder that improves over time, especially those individuals in whom there was an antecedent viral infection. Initially, nonpharmacologic measures are recommended, such as correcting hypovolemia and promoting physical conditioning. In some cases, fludrocortisone may be helpful in restoring vascular volume and, for some patients, beta blockers may be helpful in reducing the tachycardia.

Primary (Inherited) Autonomic Disorders