As discussed in previous chapters, the ANS is extensive and is involved in the function of almost every organ system. Therefore, the clinical manifestations of autonomic dysfunction are diverse. Indeed, the ANS is involved in most diseases. Any structural pathological process affecting the brain (whether infectious, inherited, neoplastic, or degenerative in nature) can result in an autonomic syndrome.

Although autonomic disorders are a well-defined group of conditions affecting the central and/or peripheral autonomic pathways, autonomic symptoms and signs are often seen in many other medical conditions or may be isolated manifestations of a limited autonomic instability (Table 7.1) [1–3]. To evaluate these conditions, it is necessary to cover each autonomic sector (cardiovascular, gastrointestinal, genitourinary, secretomotor, sudomotor, neuroimmunoendocrine), define the temporal profile, identify associated symptoms, recognize atypical symptoms as expression of autonomic dysfunction, and exclude other conditions that could mimic its manifestations. To properly study these disorders, multiple tests are needed, in addition to supportive data that often include neuroimaging, sleep studies, specific blood and urine testing, and tissue diagnosis [4].

A preliminary evaluation can be done at the bedside, at least for the most disabling symptoms of autonomic dysfunction. Significant decrement in BP without compensatory tachycardia is much worse prognostically than marked tachycardia without significant BP changes (Chap. 4). Secretomotor and sudomotor functions can be assessed by observation of the mucosae and by appreciating the presence of moisture on the skin by palpation. Hyperhidrosis is easily appreciated as sweat droplets over the skin or visibly wet garments. Occasionally, simultaneous ECG monitoring can identify an ictal bradycardia or asystole, or provide confirmation that convulsive manifestations commonly seen in syncope are secondary to the hemodynamic changes.

Symptoms suggestive of autonomic dysfunction include, but are not limited to, postural hypotension, digestive discomfort, altered intestinal, bladder or sexual function, decreased or increased sweating, dry mucous membranes, and cooling or discoloration of the extremities. Insomnia, anxiety, brain fog and chronic fatigue may be present (Table 7.1). In clinical practice, the symptoms of autonomic dysfunction are often underestimated, because they are subjective, frequently transient in healthy subjects, of slow onset and evolution, of little disability in the patient (at least in the initial stages), and difficult to treat.

Table 7.2 summarizes the most important autonomic tests that allow the various autonomic functions to be explored [1–3, 5]. Autonomic tests usually consist of physical stimuli or actions that elicit changes in sympathetic and parasympathetic activity, often reflected as BP and heart rate alterations. The Valsalva maneuver is one autonomic challenge with multiple response phases that influences, to varying degrees, both sympathetic and parasympathetic outflow. Despite consisting of a relatively simple somatomotor task, namely exhaling against a resistance to a predetermined pressure (30–40 mmHg) for a defined period (15–20 s), the cardiovascular response is separated into four distinct patterns occurring over periods of time, not including preliminary inhalation:

A hand grip, which also involves sympathetic activity increases, is another common autonomic test. Baroreceptor unloading tasks include lower body negative pressure, which requires a specialized suit, or the simpler to implement Müller’s maneuver , which is the reverse of the Valsalva manoeuver, consisting in a negative pressure in the chest and lungs after a forced expiration following by an inspiration with closed mouth and nose [5].

The cold pressor is a passive autonomic test that has the advantage of being a consistent stimulus across subjects, although the pain component may be a confounder to BP manipulation. Other tests identify changes in state that last several minutes, such as the quantitative sudomotor axon reflex test.

Head-up tilt table testing is a provocative test designed to simulate orthostatic stress and downward gravitational fluid shifts. It is classically used to diagnose neurally mediated (reflex) syncope. Tilt testing can also be used to aid in the diagnosis of other disorders of orthostatic intolerance, including postural tachycardia syndrome and orthostatic hypotension [6].

Changes in cardiac autonomic function can be tracked by several techniques. The simplest measure of cardiac autonomic status is the resting heart rate. Greater autonomic dysfunction is associated with increasing resting heart rates over time. A more robust measure of autonomic function is heart rate variability (HRV) , measured using continuous heart rate monitoring. HRV is a set of parameters that reflects interval fluctuations between sequential beats of the heart [7–9]. Measures derived from interval differences between successive beats reflect parasympathetically modulated changes in heart rate. Other HRV measures reflect the combined signaling of the two arms of the autonomic nervous system and reflect both intrinsic (e.g., baroreflex, renin–angiotensin, sleep cycles, circadian) and extrinsic (activity, rest) rhythms. In general, decreased or decreasing HRV would be a signal for worse cardiac autonomic dysfunction. However, a higher, but more disorganized, HRV pattern, detectable by certain “nonlinear” HRV measures also reflects greater cardiac autonomic dysfunction [10]. Ideally, HRV is measured using 24-h ambulatory monitoring which can capture both daytime heart rate patterns and heart rate patterns during sleep, providing insights into circadian rhythm, sleep quality, and possible sleep-disordered breathing or periodic limb movements, all of which affect cardiac autonomic functioning. However, significant clinical information can be obtained from shorter recordings performed, perhaps, at the time of clinical visits and in association with standard bedside autonomic tests.

As mentioned in Chap. 6, changes in skin conductance occur with eccrine sweating and constitute a relatively pure assay of sympathetic activity (sympathetic skin response) [11]. Alterations in sweating are mediated by cholinergic nerves and are not affected by β-adrenoceptor blockers, allowing evaluation of the sympathetic system. It consists of a potential generated by sweating in the skin in response to different stimuli, including those that produce emotional reactions [12]. An alteration in the resistance of the skin is caused and a potential is obtained.

Microneurography is a unique method of recording postganglionic sympathetic neural traffic directly from human peripheral nerves. For sympathetic microneurography, tungsten microelectrodes are inserted through the skin onto an underlying peripheral nerve, innervating either skin or skeletal muscle. Sympathetic fibers are spontaneously active and many fibers discharge in synchronized bursts of impulses. Usually, action potentials are recorded simultaneously from several fibers (multifiber activity) and presented in a mean voltage (integrated) neurogram [13].

Sympathetic neuroimaging provides an important supplement to physiological, neurochemical, and neuropharmacological approaches in the evaluation of patients with clinical autonomic disorders. Sympathetic neuroimaging to date has involved visualization of noradrenergic innervation in the left ventricular myocardium [14]. Sympathetic imaging depends on the radiolabeling of vesicles in sympathetic nerves. The most commonly used imaging agent to assess cardiac sympathetic innervation is ¹²³I-metaiodobenzylguanidine. Cardiac sympathetic neuroimaging and postmortem neuropathological findings have linked α-synucleinopathy with noradrenergic denervation in Lewy body disease. Patients with familial Parkinson’s disease from abnormalities of the gene encoding α-synuclein have cardiac sympathetic denervation.

Cutaneous punch biopsies are widely used to evaluate nociceptive C fibers in patients with suspected small-fiber neuropathy [15]. Peripheral adrenergic and cholinergic fibers innervate several cutaneous structures, such as sweat glands and arrector pili muscles, and can easily be seen with punch skin biopsies. Skin biopsies allow for both regional sampling, in diseases with patchy distribution, and the opportunity for repeated sampling in progressive disorders.

There are several ways to categorize autonomic dysfunctions, depending on the points of view from which they are considered [1, 2]. Clinical disorders of ANS can be conceptualized as focal (e.g., Horner’s syndrome, Chap. 3) or generalized, affecting several autonomic segments (such as progressive autonomic failure). Another possible pathophysiological classification of autonomic dysfunctions is based on their primary or secondary nature, as summarized in Table 7.3. In addition, it is necessary to consider whether the manifestations are predominantly due to a sympathetic, parasympathetic, or mixed dysfunction (pandysautonomia).

Some characteristic patterns, based on temporal evolution and the constellation of semiology constellation, are also important in the differential diagnosis of autonomic neuropathies. Finally, there are some neurological disorders that affect the ANS, but in most cases, they are associated with somatic nervous system involvement. ANS dysfunctions may be due to increases or decreases in autonomic control activity and may occur because of brain, spinal or peripheral nerve injuries.

The enlarged view of ANS discussed in this book leads to a classification of autonomic disorders compatible with that found in popular clinical textbooks, e.g., Low and Engstrom (Table 7.4) [3]: