Which is correct regarding the sympathetic nervous system

SNS

SNS has evolved into the treatment of choice for patients with fecal incontinence with very few exceptions. The treatment modality expanded after a benefit on bowel control was noted in patients treated with SNS for urinary incontinence. In 2011, it secured US Food and Drug Administration approval for use in patients with fecal incontinence. Although the exact mechanism of action remains unclear, SNS via direct, low-voltage stimulation of the sacral nerve roots appears to simultaneously affect multiple levels of the complex neuromuscular pathway that controls fecal continence. The implantation is carried out in two stages, both in the outpatient setting. The first stage is considered a trial phase and involves the percutaneous placement of a wire with four leads into the S3 foramen (Fig. 4). Correct lead placement is confirmed by means of fluoroscopy (Fig. 5) and intraoperative test stimulation, which should result in a contraction of the pelvic floor musculature (Bellow’s sign) and ipsilateral great toe flexion. These leads are then connected to an external stimulator. Symptoms are tracked over 2 weeks before and after the implantation. If the stimulation results in at least a 50% reduction in fecal incontinence episodes, it is considered a success, and the patient moves on to stage 2; otherwise, the temporary lead is removed. Stage 2 procedure involves the permanent implantation of the actual stimulator in the soft tissue of the buttocks just below the iliac crest (Fig. 4).

Studies have shown that definitive implantation was associated with a greater than 50% improvement in 86% to 87% of patients and with nearly perfect control in 40% of the patients. Even in the long-term analysis, the success appeared to persist, but after 3 to 5 years, a battery change is needed. The method has a favorable safety profile, and complications (e.g., pain, infection, bleeding, paresthesia) are comparably rare.

The success of SNS has caused a major paradigm shift in the workup and treatment of patients with incontinence. It has become clear that no preoperative test, but only the trial lead placement, can predict treatment successes. Therefore, the traditional recommendation to do anophysiology and pudendal nerve testing before any surgical intervention has lost regard. SNS is now indicated following failed nonoperative management of any incontinence regardless of whether there is a sphincter defect or pudendal neuropathy. Exceptions are limited to gross congenital or acquired anatomical alterations of the sacrum and pelvic floor, local tissue infections, a predictable need for magnetic resonance imaging scans, or a failed test phase.

Historical and Conceptual Overview

The term sympathetic nervous system originates in the second-century teaching of Galen that the peripheral nerves, conduits for distributing the animal spirit in the body, enable concerted, coordinated (i.e., sympathetic) functioning of body organs. The notion of the sympathetic nervous system, therefore, antedated by approximately 14 centuries Harvey's demonstration of the circulation of the blood.

The sympathetic nervous system is a major component of the autonomic nervous system. In the late nineteenth century, Langley introduced the phrase autonomic nervous system to refer to nerves emanating from cell bodies in ganglia alongside the spinal column and in the gastrointestinal-tract walls. Langley defined three components: sympathetic, with preganglionic cells in the thoracolumbar spinal cord; parasympathetic (a word he coined), with preganglionic cells in the brain stem or sacral spinal cord; and enteric, with preganglionic cells near or in the target organs. The nerves of these systems were thought to differ from those of the somatic nervous system, not only in terms of anatomy but also in terms of function. Somatic nerves mediate conscious, observable changes in skeletal muscle contraction and therefore movement, whereas autonomic nerves mediate unconscious, largely unobservable changes in smooth muscle contraction independently (autonomously) of the central nervous system.

The early-twentieth century American physiologist Walter B. Cannon introduced the word homeostasis. Cannon added a hormonal component to the autonomic nervous system when he theorized that the sympathetic nervous system and the adrenal gland worked together as a unit to maintain homeostasis in emergencies. In the 1930s, he even formally proposed that the sympathetic nervous system used the same chemical messenger – adrenaline – as did the adrenal gland (in 1946, von Euler correctly identified the sympathetic neurotransmitter in mammals as norepinephrine). Accumulating evidence supports the independent regulation of the sympathetic nervous and adrenomedullary hormonal systems, refuting the concept of a unitary sympathoadrenal system. Nevertheless, Cannon's views about the unitary function of the neural and hormonal components of the sympathoadrenal system prevail in stress research.

Sweating, whether to control body temperature (thermoregulatory), evoked by eating spicy food (gustatory), or accompanying fear or anxiety (emotional), is mediated by the sympathetic cholinergic system, in which acetylcholine rather than norepinephrine is the chemical messenger. The autonomic nervous system, therefore, can be viewed as having five components: sympathetic noradrenergic, sympathetic cholinergic, parasympathetic cholinergic, adrenomedullary, and enteric.

Location of Damage to the Sympathetic Pathway

After the diagnosis of Horner's syndrome is made, localizing whether the damage is along the preganglionic or postganglionic sympathetic pathway helps direct imaging, if indicated. Horner's syndrome sometimes manifests so characteristically that further efforts to localize the lesion are superfluous, as with patients with cluster headaches or patients with a history of surgery or trauma along the sympathetic pathway. Localization of a sympathetic lesion is a question of considerable clinical importance because many postganglionic defects are caused by vascular headache syndromes, cavernous sinus pathology, or carotid dissections, and preganglionic lesions sometimes result from malignant tumors or strokes to the central sympathetic location in the brain. These findings can assist the radiologist in interpretation of any diagnostic imaging. Pharmacological testing with hydroxyamphetamine drops can be helpful in localizing the lesion as well.

Hydroxyamphetamine releases norepinephrine from storage vesicles in the postganglionic sympathetic nerve endings at the iris dilator muscle. When the lesion is postganglionic, the third order nerve is dead, and no norepinephrine stores are available for release at the iris. When the lesion is complete, the pupil does not dilate at all. However, the dying neurons and their stores of norepinephrine may last for almost 1 week from the onset of damage. Therefore, a hydroxyamphetamine test administered within 1 week of a postganglionic lesion may give a false preganglionic localization if some of the norepinephrine stores remain. When Horner's syndrome is caused by preganglionic or central lesions, the pupils dilate normally because the postganglionic third order neuron and its stores of norepinephrine, although disconnected, are still intact.

To perform the hydroxyamphetamine test, the pupil diameters are measured before and 60 minutes after hydroxyamphetamine drops have been placed in both eyes. The change in anisocoria in room light is noted. If the affected pupil—the smaller one—dilates less compared with the normal pupil, an increase in anisocoria occurs, and the lesion is in the postganglionic neuron. If the smaller pupil now dilates so much that it becomes the larger pupil, the lesion is preganglionic and the postganglionic neuron is intact. The examiner must wait at least 48 hours after cocaine has been used before the administration of hydroxyamphetamine; cocaine inhibits the uptake of hydroxyamphetamine into the presynaptic sympathetic nerve terminal and seems to block its effectiveness. In general, if the anisocoria increases by at least 0.5 mm after hydroxyamphetamine administration, the lesion is most likely postganglionic. A decrease in anisocoria points toward a preganglionic location of the lesion. However, hydroxyamphetamine is no longer commercially available, and there are rare reports of false localization with hydroxyamphetamine. For these reasons, many clinicians forgo further localizing with hydroxyamphetamine and image the entire sympathetic pathway unless history or associated signs and symptoms clearly localize the lesion. For instance, acute Horner's syndrome with associated ipsilateral neck or facial pain requires urgent imaging of the neck for evaluation of a carotid dissection.

Electrodermal Activity

SNS activation is also measured through electrodermal activity (EDA), or skin conductance. When stressful situations activate the SNS, sweat rises toward the skin surface and eccrine sweat glands act as resistors. The hydration of the skin associated with the increase in sweat creates greater skin conductance and lower skin resistance. Researchers place two electrodes on the skin to measure skin resistance; the skin conductance measurement assesses the extent to which electrical conduction is increased and skin resistance is decreased. Similar to studies of PEP, electrodermal responsivity is related to emotional expressions (Cole et al., 1996) and behavior problems (El-Sheikh et al., 2011).

Adrenal Medullary Sympathetic Hormone Excess: Pheochromocytoma

Less than 0.1% of all cases of hypertension are caused by pheochromocytomas, or catecholamine-producing tumors derived from chromaffin tissue.54 Nevertheless, these tumors are clearly important to the anesthesiologist as previously 25% to 50% of hospital deaths in patients with pheochromocytoma occurred during induction of anesthesia or during operative procedures for other causes.55 This high mortality has been reduced with the improvements in anesthesia management during our current era.55a Although usually found in the adrenal medulla, these vascular tumors can occur anywhere (referred to as paragangliomas), with a proportion of up to 20%.55b Malignant spread, which occurs in less than 15% of pheochromocytomas, usually proceeds to venous and lymphatic channels with a predisposition for the liver. This tumor is occasionally familial or part of the multiglandular-neoplastic syndrome known as multiple endocrine adenoma type IIa or type IIb, and is manifested as an autosomal dominant trait. Type IIa consists of medullary carcinoma of the thyroid, parathyroid adenoma or hyperplasia, and pheochromocytoma. What used to be called type IIb is now often called pheochromocytoma in association with phakomatoses such as von Recklinghausen neurofibromatosis and von Hippel–Lindau disease with cerebellar hemangioblastoma. Frequently, bilateral tumors are found in the familial form. Localization of tumors can be achieved by MRI or CT, metaiodobenzylguanidine nuclear scanning, ultrasonography, or intravenous pyelography (in decreasing order of combined sensitivity and specificity).

Symptoms and signs that may be solicited before surgery or procedures and are suggestive of pheochromocytoma are as follows: excessive sweating; headache; hypertension; orthostatic hypotension; previous hypertensive or arrhythmic response to induction of anesthesia or to abdominal examination; paroxysmal attacks of sweating, headache, tachycardia, and hypertension; glucose intolerance; polycythemia; weight loss; and psychological abnormalities. In fact, the occurrence of combined symptoms of paroxysmal headache, sweating, and hypertension is probably a more sensitive and specific indicator than any one biochemical test for pheochromocytoma (Table 32.4).

The value of preoperative and preprocedure adrenergic receptor blocking drugs probably justifies their use as these drugs may reduce the perioperative complications of hypertensive crisis, the wide arterial blood pressure fluctuations during tumor manipulation (especially until venous drainage is obliterated), and the myocardial dysfunction. Mortality is decreased with resection of pheochromocytoma (from 40% to 60% to the current 0% to 6%) when adrenergic receptor blockade is introduced as preoperative and preprocedure preparatory therapy for such patients.56-60

Association between RLS/PLMs and sympathetic activation

Sympathetic nervous system (SNS) activity may contribute to generating the periodicity of PLMs. Two patients with insomnia who were found to have PLMs on PSG, also complained of cold feet. After a plethysmographic assessment demonstrated blunted pulses, warming of the lower extremity improved the pulses suggesting vasoconstriction as a mediator of the pulse abnormality. Treatment with phenoxybenzamine, a post-synaptic α-1 blocker, resulted in improvement of symptoms of cold feet as well as the PLMs suggesting sympathetic nervous system involvement in the vascular constriction as well as the periodicity of the PLMs. The authors pointed out that the SNS inherent periodicity of 20–40 s reflected that typically seen with PLMs (Ware et al., 1988). In addition, patients with RLS have decreased cardiovagal baroreceptor gain and increased calf vascular resistance, which may be mediated by the sympathetic nervous system (Bertisch et al., 2016).

In patients with restless legs syndrome, both systolic and diastolic blood pressures rise following a periodic limb movement during sleep with the peak occurring about 6–7 s following the limb movement. The average change in SBP was 16.7 mmHg when the limb movement was associated with a cortical arousal, and 11.2 mmHg when the limb movement was not. The consistent association between rise in blood pressure and limb movements supports the hypothesis that periodic limb movements are a component of an autonomic surge (Siddiqui et al., 2007). Another analysis of blood pressure changes associated with PLMs also found increases in systolic and diastolic pressures independent of whether micro-arousals were present, or not. Increases in blood pressures were noted several heartbeats after the PLM occurred, and were greater when micro-arousals were associated with the PLMs, than when they were not. The responses in blood pressures were greater with advancing age, longer history of RLS, and by longer duration of the associated micro-arousal (Pennestri et al., 2007).

PLMs have been shown to associate with hypertension severity. In one study that grouped patients according to the severity of their hypertension, those with more severe hypertension demonstrated statistically more PLMs than those with less severe hypertension. Age influenced the occurrence of PLMs, with patients over 50 years-old demonstrating more PLMs, and those with PLMs demonstrating a higher mean age than those without PLMs, but not the association between PLMs and hypertension. The presence, or absence of arousals did not affect the association between PLMs and hypertension severity (Espinar-Sierra et al., 1997).

5.18.5 Conclusions

SNS plays an intriguing role in maintaining pain in certain conditions. Complex regional pain syndromes are prime example of such states. Selective sympathetic blocks are commonly used to diagnose a subset of patients with a predominant sympathetically maintained pain state. In order to avoid false-positive diagnosis, at least two different diagnostic tests should be implicated on separate days to confirm the diagnosis. Treatment options that have shown some promising results include local anesthetic sympathetic blocks, SCS, radiofrequency techniques, and surgical sympathectomy in early stages. Visceral pain of pancreatic origin responds well to chemical neurolytic blocks. More randomized trials are warranted to prove long-term efficacy of neuromodulation as well as neurodestructive techniques.

SNS and the SAM Axis

The SNS influences the cardiovascular system, the gastrointestinal (GI) tract, respiration, renal, endocrine, and other systems, while the parasympathetic nervous system contributes by “withdrawing” and inhibiting the SNS. The SNS response is mediated by the locus coeruleus (LC)/noradrenergic system, comprising the noradrenergic cells of the medulla and pons. The CE projects to the brain stem to increase noradrenaline (NA) release from sympathetic nerve endings, sympathetic activation, and activation of the adrenal medulla, resulting in increased adrenaline and NA levels, arousal, and vigilance, that is, enhanced processing of external cues. The SAM system releases catecholamines (mostly adrenaline) into the bloodstream while the SNS with cholinergic preganglionic fibers releases NA from postganglionic axons. SNS innervation of peripheral organs is mediated by efferent preganglionic fibers, with cell bodies in the intermediolateral column of the spinal cord. These synapse in the sympathetic ganglia with postganglionic neurons, which innervate the vascular smooth muscle, heart, skeletal muscles, gut, kidney, fat, etc. Blood pressure and heart rate are elevated and energy resources are diverted to the musculature and away from vegetative functions.

At the same time, the hypothalamus is activated by the amygdala (largely indirectly; Herman et al., 2003) to release corticotropin-releasing hormone (CRH), and HPA activation ensues. Thus the two arms of the stress response system are both closely connected with amygdala and brain-stem function. Through its projections to the amygdala, the SNS enhances long-term storage of aversive emotional memories in the hippocampus and striatum. Noradrenergic responses to stressors may be modulated by higher centers such as the mesocortical/mesolimbic systems (influencing affect and anticipation); the amygdala and hippocampus, modulating the stress output (initiation, propagation, and termination of the response); and the arcuate nucleus, modulating pain.

Abstract

The sympathetic nervous system plays important roles in the beat-to-beat control of blood pressure, the control of blood flow through various organs and the maintenance of core temperature through thermoregulatory processes. The development of microneurography, in which nerve activity can be recorded directly from intraneural microelectrodes inserted percutaneously into a peripheral nerve in awake human subjects, has provided a wealth of information on the control of sympathetic outflow to muscle and skin. Although not intended to be diagnostic, recordings of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) in different disease states have increased our understanding of the operation of the sympathetic nervous system. And while quantification of sympathetic nerve activity is still largely limited to measures of burst frequency (bursts/minute) and burst incidence (bursts/100 heart beats), the development of single-unit recordings of MSNA and SSNA have provided more detailed information on how the sympathetic nervous system grades its output. This chapter reviews the development of sympathetic microneurography and its application in health and disease.

The nervous system promotes regeneration of other important niche cells: Endothelium and nestin + cells

The sympathetic nervous system (SNS) also plays a significant role in promoting hematopoietic regeneration after myeloablation. Indeed, chemotherapies that damage nerves also compromise hematopoietic regeneration while protection of sympathetic nerve fibers from apoptosis via Trp53 deletion or induced neuroregeneration via 4-methylcatechol or glial-derived neurotrophic factor treatment promotes hematopoietic regeneration. The SNS appears to promote hematopoietic regeneration indirectly by activating β-adrenergic signaling and secreting neuropeptides in the niche. Denervation of the BM or blocking adrenergic signaling results in an increased loss of BM endothelial and Nestin + mesenchymal cells following myeloablation, which stifles hematopoietic regeneration. Nestin + cells are key sources of CXCL12 during homeostasis to which HSC home after lethal irradiation and transplant. Nestin + cells crosstalk with macrophages in the h-niche and maintain HSC retention. In vitro, macrophages respond to Neuropeptide Y (NPY), a secreted neurotransmitter from sympathetic nerves, via the NPY receptor, Y1. Evidence suggests NPY, acting via the macrophage Y1 receptor, induces release of TGF-β to suppress HSC cell cycling; preventing premature exhaustion. Whether these findings translate in vivo is unclear. Indeed, NPY treatment reduces irradiation-induced nerve damage and improves engraftment. HSC cannot efficiently engraft the BM of mice lacking NPY due to reduced homing and increased apoptosis in both stromal populations and HSC themselves. Thus, NPY is a critical regulator of HSC during homeostasis and regeneration, making it ripe for clinical exploitation to improve outcomes in patients.

A better understanding of how the nervous system regulates HSC is likely to illuminate additional factors that could be exploited to improve HSC engraftment and BM recovery. In sum, β-adrenergic signaling and NPY are key SNS-derived players that regulate the r-niche (Fig. 1).