Fig. 2.19 Purinergic junction: scheme of synthesis, storage, release, and inactivation of autonomic transmitters. (From [47], with permission)
Activity of the autonomic nervous system can be evaluated directly or indirectly. In the sympathetic nervous system this can be performed by electrophysiological (with sympathetic microneurography) or biochemical techniques. The latter include measurement of catecholamines and their metabolites in urine and plasma, spillover techniques using tritiated catecholamines, and use of substances such as metaiodobenzylguanidine (MIBG, a γ-emitter) or 6-[18F] fluorodopamine (a positron emitter) that are taken up by postganglionic sympathetic nerves and detected by appropriate scanning techniques. However, there are limitations to each of these techniques. Sympathetic microneurography is dependent upon insertion of a fine tungsten microelectrode into a peripheral nerve and into a muscle or skin sympathetic fascicle (Fig. 2.20). It is an invasive technique, although safe in experienced hands; there are difficulties with electrode placement in autonomic disorders causing underactivity or inactivity. Urinary and plasma catecholamines (Fig. 2.21) do not control for small or rapid changes and are affected by metabolism and uptake effects, among other factors. The spillover techniques are invasiveand involve direct cannulation of blood vessels, but provide measurement of change in sympathetic activity, especially in key organs such as the heart, kidneys, and brain (Fig. 2.22). The imaging techniques using MIBG or fluorodopamine are noninvasive but semiquantitative. These different techniques are used extensively in research but not usually in the routine clinical setting, where tests of function are utilized that are dependent not only on activity of the autonomic nerves but also on the response of target organs.
Fig. 2.20 Relationship between spontaneous fluctuations of blood pressure and muscle nerve sympathetic activity recorded in the right peroneal nerve. Arterial baroreflex activity accounts for the pulse synchrony of nerve activity and the inverse relationship to blood pressure fluctuations. The asterisk indicates a diastolic blood pressure fall due to sudden atrioventricular block. Stippling indicates corresponding sequences of bursts and heart beats. (From [48], with permission)
An outline of investigational approaches for relevant systems is provided in Table 2.4. A detailed history and clinical examination, to include all organs and integrative system function affected by autonomic dysfunction, helps guide the choice of testing. The effects of autonomic underactivity and overactivity should be considered. Cardiovascular autonomic assessment often provides a readily assessable and noninvasive means of screening for dysfunction. A variety of cardiovascular tests are helpful in distinguishing between sympathetic and parasympathetic function (Figs. 2.23, 2.24). A cardinal feature of sympathetic denervation often is orthostatic (postural) hypotension (Fig. 2.25), which will not be detected unless measurements are made in the supine and head-up (sitting or standing) positions. These measurements often are performed when there is clinical suspicion, such as when syncope is reported. However, there can be a variety of symptoms resulting from, or in association with, orthostatic hypotension (Table 2.5) that have multiple causes and this may result in failure to consider orthostatic hypotension and thus measure blood pressure before and after postural challenge. Orthostatic hypotension may occur later in the course of disease, as in diabetes mellitus, where cardiac parasympathetic denervation often is anearly feature of autonomic neuropathy. When orthostatic hypotension is present, consideration also should be given to a range of causative nonneurogenic factors (Table 2.6).
Table 2.4 Outline of investigations in autonomic failure
| Cardiovascular | |
| Physiological | Head-up tilt (45°); standing; Valsalva maneuverPressor stimuli: Isometric exercise, cold pressor, mental arithmeticHeart rate responses: deep breathing, hyperventilation, standing, head-up tilt, 30:15 ratioLiquid meal challengeExercise testingCarotid sinus massage |
| Biochemical | Plasma norepinephrine: supine and head-up tilt or standing; urinary catecholamines; plasma renin activity and aldosterone |
| Pharmacological | Norepinephrine: a-adrenoceptors, vascularIsoprenaline: (β-adrenoceptors, vascular and cardiacTyramine: pressor and norepinephrine responseEdrophonium: norepinephrine responseAtropine: parasympathetic cardiac blockade |
| Sudomotor | Central regulation: thermoregulatory sweat testSweat gland response: intradermal acetylcholine, quantitative sudomotor axon reflex test (Q-SART).localized sweat testSympathetic skin response |
| Gastrointestinal | Barium studies, video-cine-fluoroscopy, endoscopy, gastric emptying studies |
| Renal function and urinary tract | Day and night urine volumes and sodium/potassium excretionUrodynamlc studies, intravenous urography, ultrasound examination, sphincter electromyography |
| Sexual function | Penile plethysmographyIntracavernosal papaverine |
| Respiratory | LaryngoscopySleep studies to assess apnea/oxygen desaturation |
| Eye | Lachrymal function: Schirmer's testPupillary function: pharmacological and physiological |
Adapted from [49]
A variety of other tests related to stimuli in daily life need to be considered in relation to diagnosis, understanding pathophysiological mechanisms, and management. Examples include the effects of food and exercise among other factors (Table 2.7) that unmask or exaggerate orthostatic hypotension when there is sympathetic vasoconstrictor failure. Food can causea marked fall in blood pressure because of splanchnic vasodilatation and an inability to compensate in other vascular regions: exercise causes vasodilatation in working muscles. Ambulatory 24-hour blood pressure (Fig. 2.26) and heart rate profiles are of value as lack of the expected nocturnal circadian fall indicates autonomic failure; with suitable protocols, orthostatic, postprandial, and exercise-induced hypotension can be evaluated with these ambulatory techniques in the home setting. Spectral analytical techniques provide further information on the differences between sympathetic and parasympathetic control of heart rate and blood pressure, and can assess respiratory influences over heart rate, in particular.
Sudomotor testing should include evaluation of gustatory sweating when relevant. In combination with neurophysiological tests, the sympathetic skin response is of value in determining sympathetic cholinergic activation (Fig. 2.27). Details of tests affecting other systems can be obtained from various textbooks [46,52,53].
The evaluation of central autonomic activity and function is separately described as there are difficulties in accurately making measurements noninvasively. Recently, however, various technological and analytical advances have been utilized to advantage. Neuroimaging using widely available techniques such as brain magnetic resonance imaging is repeatable and reproducible and can determine morphology of even small structures such as the insular cortex, amygdala, and pontine regions; thus, in central autonomic disorders such as multiple system atrophy, discrete abnormalities are discernible in the brainstem. Further amplification of neuronal involvement may be obtained by magnetic resonance spectroscopy, although abnormalities have been described mainly in the basal ganglia. Of importance are the techniques of positron emission tomography (PET) and functional MRI (fMRI) scanning.