Autonomic disturbances are a characteristic feature of certain neurologic disorders; may be a cause of death in others; and sometimes complicate general medical disorders, such as diabetes mellitus. For most clinical purposes, autonomic function is evaluated by a number of simple noninvasive tests. These tests have an important role in several clinical contexts. First, they help to confirm a clinical diagnosis of dysautonomia and to exclude other causes of symptoms. Second, they provide an indication of the extent and severity of autonomic involvement and indicate whether the sympathetic and parasympathetic divisions are affected equally or whether one is involved selectively. Third, they may permit the site of the lesion to be localized more precisely, although this sometimes requires more sophisticated or invasive studies. Finally, autonomic function tests may be helpful in the evaluation of small-fiber neuropathies. In this chapter, attention is directed primarily at investigations that can be undertaken conveniently in a clinical neurophysiology laboratory. The enteric component of the autonomic nervous system is also important, but it will not be discussed here because it is usually not the focus of clinical neurophysiologists.
Anatomy
Details of the anatomy of the autonomic nervous system are provided in standard textbooks; only a short summary of certain aspects of clinical relevance is provided here to facilitate understanding of clinical test procedures and their interpretation.
Afferent Pathways and Central Structures
Autonomic afferent fibers pass along autonomic or somatic peripheral nerves to the central nervous system (CNS), but their precise pathways have not been well defined. Fibers from the retina pass along the optic nerve and tract to the pretectal nucleus and then to pupilloconstrictor neurons in the Edinger–Westphal nucleus. The trigeminal nerve carries afferent fibers from the cornea and the nasal and oropharyngeal mucosa to the trigeminal nuclei and the nucleus tractus solitarius; their activation causes lacrimation and nasal and oral secretions. The glossopharyngeal and vagus nerves carry afferent impulses from baroreceptors in the carotid sinus and aortic arch to the brainstem ( Fig. 21-1 ). Cardiac afferent fibers also pass in the vagus nerve and sympathetic nerves. Afferent impulses travel in the vagus nerve from the tracheobronchial tree and abdominal viscera to the nodose ganglion and nucleus tractus solitarius. Somatic afferent fibers also influence autonomic activity. Sensory neurons projecting to the sympathetic system reside in the dorsal root ganglia and relay information to the dorsal horns of the spinal cord.
A number of regions within the CNS have an important role in modulating autonomic function. These include the frontal and parietal cortical regions, which may influence heart, blood pressure, and respiratory functions. The cingulate cortex is involved in controlling sphincter (bladder and bowel) functions, and bilateral lesions therefore may lead to sphincter disturbances. The temporal lobe and amygdala have autonomic functions, and autonomic features are well-known accompaniments of seizures arising in these regions. The hypothalamus, cerebellum, and various brainstem nuclei also have major roles. Afferent fibers from arterial baroreceptors and chemoreceptors end in the nucleus tractus solitarius in the dorsomedial medulla, and this nucleus also receives input from neocortical, forebrain, diencephalic, and rostral brainstem structures (see Fig. 21-1 ). In turn, it projects to the nucleus ambiguus and dorsal nucleus of the vagus and to the lateral reticular formation; it thus influences the cardiovascular and gastrointestinal systems. Various pontine and medullary regions are involved in the regulation of ventilation.
Sympathetic Efferent Pathways
Descending fibers from the brainstem conduct impulses to the preganglionic sympathetic neurons, which are located in the intermediolateral columns of the spinal cord between about T1 and L2. The axons of these neurons pass to the sympathetic trunk in the white rami communicantes ( Fig. 21-2 ). The sympathetic trunk, on each side of the vertebral column, consists of a chain of ganglia connected by longitudinally running fibers. Within the sympathetic trunk, the axons synapse in the paravertebral ganglia with second-order neurons. Some of the preganglionic axons pass up or down in the sympathetic trunk to ganglia at other levels before synapsing. There are 3 paired sympathetic ganglia in the cervical region, 12 in the thoracic region, 4 in the lumbar region, 4 or 5 sacrally, and 1 unpaired ganglion in the coccygeal region. The inferior cervical and first thoracic ganglia may fuse to form the stellate ganglion. Unmyelinated postganglionic fibers pass back to the spinal nerves in the gray rami communicantes or form perivascular plexuses along major arteries as they pass to their final destinations.
Some preganglionic sympathetic fibers pass through the sympathetic ganglia without a synapse to form the splanchnic nerves; these fibers synapse in the prevertebral (preaortic) ganglia (i.e., the celiac, superior mesenteric, and inferior mesenteric ganglia), from which postganglionic fibers pass to the viscera in the hypogastric, splanchnic, and mesenteric plexuses ( Table 21-1 ).
| Outflow | Target Structure | ||
|---|---|---|---|
| Second-order neuron in paravertebral ganglia | |||
| Eyes Salivary glands Face Head Upper limbs Heart Tracheobronchial tree Lungs Pulmonary vessels Trunk Lower limbs | |||
| Second-order neuron in prevertebral ganglia | |||
| Nerve | Ganglion | Plexus | |
| Greater splanchnic | Celiac | Hypogastric | Liver, bile ducts, gallbladder Pancreas Spleen Stomach Small intestine Proximal colon |
| Lesser splanchnic | Superior mesenteric | Splanchnic | Small intestine Colon |
| Lumbar splanchnic | Inferior mesenteric | Mesenteric | Distal colon Bladder Genitalia |
The head and neck are innervated by preganglionic neurons in the T1 and T2 segments through the superior cervical ganglion and the upper four cervical spinal nerves. The upper limb is supplied by preganglionic neurons in the T2 to T8 segments and the stellate ganglion, with varying contributions from the middle cervical and upper thoracic ganglia. The legs are supplied from the T10 to L2 segments through the paravertebral ganglia. Postganglionic sympathetic fibers differ in their properties, depending on their target organ. Thus, cutaneous sympathetic fibers have differing conduction velocities, depending on whether they are vasomotor or sudomotor in function.
Parasympathetic Efferent Pathways
The parasympathetic cranial and sacral outflow is summarized in Table 21-2 . The peripheral ganglia are located close to the target organs so that the postganglionic pathways are short.
| Nerve | Peripheral Ganglia | Target Structure | |
|---|---|---|---|
| Brainstem outflow | Oculomotor | Ciliary | Eye |
| Facial | Pterygopalatine | Palatine glands | |
| Submandibular | Submaxillary glands Sublingual glands | ||
| Glossopharyngeal | Otic | Parotid glands | |
| Vagus | Ganglia or plexuses related to target organs | Heart Airways and lungs Abdominal viscera | |
| Sacral outflow (S2–S4) | Pelvic | Pelvic | Distal colon and rectum |
| Bladder | |||
| Genitalia |
Clinical aspects of dysautonomia
The clinical features of dysautonomia are described in standard textbooks, but a brief summary is provided here as they point to the need for investigation and are reflected by the manner in which patients are investigated. The most disabling feature is probably an impaired regulation of blood pressure, especially postural hypotension or paroxysmal hypertension. Other cardiovascular abnormalities include syncope, disturbances of cardiac rhythm, and facial flushing. Disturbances of sweating are also common and are manifest by impaired thermoregulatory sweating (anhidrosis or hypohidrosis that may lead to hyperpyrexia if the ambient temperature is high) or hyperhidrosis. Symptoms of gastrointestinal dysfunction include dysphagia from esophageal peristalsis or impaired relaxation of the esophageal sphincter; early satiety, postprandial discomfort, gastric fullness or distension, and vomiting from gastroparesis; and intestinal pseudo-obstruction, constipation, or diarrhea from altered intestinal motility. Urinary frequency, urgency, and incontinence are features of bladder involvement in some patients, whereas hesitancy, retention, or overflow incontinence occurs in other patients, depending on the site of the lesion. Fecal incontinence may occur. Sexual disturbances are common. Erectile dysfunction may have many causes, including an underlying dysautonomia. Ejaculatory failure may also occur. Lesions of the sacral roots or pelvic nerves may be responsible and, in women, may lead to a failure of arousal. The effect of cord lesions depends on their completeness and segmental level. Neuro-ophthalmologic disturbances are other manifestations of a dysautonomia that are well described and beyond the scope of this chapter.
A questionnaire for measuring autonomic symptoms has been developed and validated. It may be useful for assessing autonomic symptoms in clinical trials and epidemiologic studies.
In patients being evaluated for symptoms suggestive of dysautonomia, non-neurologic causes of their complaints require exclusion because they are often reversible. Clinical evaluation is directed with this in mind. The history may suggest an iatrogenic or toxic cause. The neurologic examination may suggest the cause of a dysautonomia. In particular, it may reveal evidence of a polyneuropathy or of a focal CNS lesion, or a combination of signs (parkinsonism with or without upper or lower motor neuron or cerebellar signs) indicative of a degenerative disorder (e.g., multisystem atrophy).
Tests of autonomic function
Involvement of the adrenergic system is tested by assessing peripheral vasomotor function and blood-pressure control under various circumstances; sympathetic cholinergic function by measures of thermoregulatory sweating; and parasympathetic impairment primarily by the heart rate responses to various maneuvers.
Cardiovascular Tests
Tests of cardiovascular function are important and provide information about both the parasympathetic and sympathetic divisions of the autonomic nervous system.
Heart Rate Variation
In normal resting subjects the heart rate is determined mainly by background vagal activity. The laboratory tests of heart rate variation are therefore mainly tests of parasympathetic function.
Heart Rate Variation with Breathing
An increase in heart rate occurs during inspiration because of decreased cardiac vagal activity; thus, it is blocked by atropine but not by propranolol. The variation in heart rate that occurs depends on the rate and depth of breathing. The test therefore must be standardized if it is to be used for clinical purposes. Normal values are affected by age, which must also be taken into account. The difference between the maximum and minimum heart rate during breathing decreases with increasing age and is diminished or absent in diabetes and other disorders that affect central or peripheral autonomic pathways, as shown in Figure 21-3 .
For clinical purposes, the recumbent patient is asked to rest quietly for 5 minutes, and then is asked to take deep breaths at the rate of six per minute, for 1 minute. The timing of the breaths can be directed verbally or by any other convenient means. The heart rate can be measured with a rate monitor or by recording the RR intervals on an electrocardiogram (ECG). The ECG may be displayed on a chart recorder or on standard electromyographic equipment.
If the heart rate is measured directly, the difference between the highest and lowest rate during the minute of deep breathing is determined. When the ECG is recorded, several different measurements of RR variation may be made. The measurements made most commonly are of (1) the difference between the longest and the shortest RR interval during the period of deep breathing; and (2) the expiratory/inspiratory (E/I) ratio, which is the ratio of the mean of the maximum RR intervals in expiration to the mean of the minimum RR intervals in inspiration.
The normal range of heart rate variation is age dependent, but normal subjects generally have differences in heart rate exceeding 15 beats per minute. Values of less than 10 beats per minute are abnormal. From a review of the existing literature, Freeman indicated a likely decline in heart rate variability of 3 to 5 beats per minute per decade in normal subjects. The use of a single normal value regardless of age therefore reduces the utility of the test, leading to false-negative results in younger patients and false-positive results in older subjects. The E/I ratio decreases with age, but up to the age of 40 years, ratios less than 1.2 may be regarded as abnormal.
Other factors affecting the results in normal subjects include the time of the test (with increased heart rate variability occurring at night), body weight, physical fitness, medication, and body position. If possible, anticholinergic medications (including over-the-counter cold medications) and antidepressants should not be taken for at least 48 hours before testing, and patients should not drink caffeinated or alcoholic beverages or smoke tobacco for 3 hours before testing.
Heart Rate Response to Change in Posture
Immediate Increase in Heart Rate with Standing
Heart rate and blood pressure responses to postural change can be measured conveniently on a tilt-table. The patient lies supine until consistent values are obtained for at least 5 (preferably 10) minutes. The patient then is tilted to be in a 60-degree head-up position and the heart rate and blood pressure are monitored. The normal decline in systolic and diastolic pressures should not exceed 25 and 10 mmHg, respectively. The heart rate normally increases by about 10 to 30 beats per minute, but the response declines with age.
30:15 Ratio
On changing from a recumbent to a standing position, a tachycardia normally occurs and is followed after about 20 seconds by a bradycardia that reaches a relatively stable rate at about the 30th beat after standing ( Fig. 21-4 ). The ratio of the RR intervals that correspond to the 30th and 15th heartbeats is therefore used widely as a measure of parasympathetic function. This 30:15 ratio decreases with age, but in young adults a ratio of less than 1.04 is regarded as abnormal. The ratio of the absolute maximum to minimum RR interval is sometimes preferred. Atropine blocks the heart rate response to standing, indicating that it depends on vagal innervation of the heart. The biphasic response is not present with passive tilting.
Power Spectral Analysis of Heart Rate
Various modifications of heart rate testing have been described but are not in widespread use. Power spectral analysis has been described of the heart rate at rest and after postural change. Two major peaks of interest on the power spectrum occur at rest: a high-frequency peak (greater than 0.15 Hz) representing heart rate changes with respiration (parasympathetic activity), and a low-frequency peak (at 0.05 to 0.15 Hz) that reflects sympathetic and parasympathetic activity. Another component, at very low frequency (less than 0.05 Hz), also occurs, but its physiologic origin is unclear. A shift in the power spectrum from high to low frequencies occurs with a change in posture to the upright position and may reflect sympathetic activation. Although the results of power spectral analysis may correlate with the results of other tests of autonomic function, the lack of correlation between commonly used indices from power spectral analysis of heart rate variability and cardiac norepinephrine spillover casts doubt on the validity of such analysis to indicate cardiac sympathetic tone.
Response to the Valsalva Maneuver
The Valsalva maneuver consists of a forced expiration against a closed glottis or mouthpiece with a calibrated air-leak. Characteristic changes in heart rate and blood pressure occur during and after performance of the maneuver and relate to changes in cardiac vagal efferent and sympathetic vasomotor activity as a result of stimulation of carotid sinus and aortic arch baroreceptors and other intrathoracic stretch receptors. For clinical purposes, it may be adequate simply to record the heart rate responses with a heart rate monitor ( Fig. 21-5 ) or an ECG. For more detailed information of the changes in heart rate and blood pressure, however, it is necessary to use a servo-plethysmomanometer device (Finapres) or record from an intra-arterial needle ( Fig. 21-6 ).
The test is performed with the subject in a semirecumbent position with a rubber clip over the nose. The subject is then required to blow into a mouthpiece (with a calibrated air-leak) connected to a mercury manometer and to maintain an expiratory pressure of 40 mmHg for 15 seconds while the heart rate is recorded. The normal response has four stages. Stages 1 and 3 are artifactual and are characterized by an increase (stage 1) or a decline (stage 3) in blood pressure because of the increase or decrease, respectively, in intrathoracic pressure at the beginning and end of the maneuver. In stage 2, the reduction in venous return leads to a progressive decline in systolic, diastolic, and pulse pressure, accompanied by a tachycardia resulting from increased cardiac sympathetic activity. The decline in blood pressure is arrested after about 5 to 8 seconds by a reflex vasoconstriction. With release of the blow at the end of the maneuver, the artifactual decline in mean blood pressure as a result of the release of intrathoracic pressure (stage 3) is followed by a rebound in blood pressure to above resting levels because of the persisting peripheral vasoconstriction and the increased cardiac output that follows the increased venous return to the heart. This overshoot in the blood pressure, which varies in extent depending upon age, is accompanied by a compensatory, vagally induced bradycardia.
Abnormalities of the Valsalva response in dysautonomic patients may take the form of a loss of the tachycardia in stage 2 or of the bradycardia in stage 4; or a lower heart rate in stage 2 than in stage 4. Other abnormalities include a decline in mean blood pressure in stage 2 to less than 50 percent of the resting mean pressure or loss of the overshoot in systolic pressure in stage 4 (see Fig. 21-6 ). With isolated impairment of efferent sympathetic vasoconstriction, the blood pressure fails to show an overshoot in stage 4, and consequently there is no compensatory bradycardia despite otherwise intact baroreflex pathways.
When the response to the Valsalva maneuver is studied simply by recording the ECG, the Valsalva ratio is calculated by dividing the longest interbeat interval occurring after the maneuver by the shortest interbeat interval during it. The highest ratio from three successive attempts, each separated by 2 minutes, is recorded. The ratio reflects both parasympathetic (vagal) and sympathetic function. The normal range of values depends on age, the duration of the forced expiration, and the extent to which intrathoracic pressure is increased. A value of 1.1 or less is regarded commonly as abnormal and a value greater than 1.2 as normal, but in normal subjects younger than 40 years the ratio usually exceeds 1.4. Low values sometimes are recorded in patients with heart and lung disease. The Valsalva ratio is sometimes normal when the blood pressure response is abnormal.
Blood Pressure Variation
Change in Posture
The effect of postural change on blood pressure is important. The blood pressure is recorded with the subject supine and at rest for at least 10 minutes. The patient then stands with the arm held horizontally to avoid the hydrostatic effect of the column of blood in the dependent arm leading to a falsely elevated blood pressure. The blood pressure is taken immediately on standing and then at 1-minute intervals for 5 minutes. In normal subjects a slight decline in systolic pressure may occur, and diastolic pressure typically increases slightly. A decline that is greater than 20 mmHg in systolic pressure or 10 mmHg in diastolic pressure within 3 minutes of gaining an upright posture generally is regarded as abnormal.
A tilt-table can also be used to evaluate postural changes in blood pressure, but the response may differ from that obtained by standing because there is less enhancement of the venous return to the heart by contraction of leg and abdominal muscles, and thus greater peripheral pooling of blood. After the patient has been supine for 10 minutes, the table is tilted to an angle of at least 60 degrees, and the patient remains in this upright position for 10 minutes. Blood pressure can be measured with a sphygmomanometer or by continuous recordings from digital arteries using the Finapres device mentioned earlier, which accurately records pressure changes. Prolonged testing (for up to 60 minutes) on a tilt-table at an angle of at least 60 degrees is being used increasingly to evaluate patients with suspected syncope.
The measurement of blood pressure in the sitting and standing positions actually has low diagnostic accuracy, and the more time-consuming method of head-up tilt-testing is preferred. Many studies have shown that blood pressure changes with posture are unrelated to age, but there is no agreement on this point and asymptomatic postural hypotension is common in elderly patients. Postural hypotension occurs in a variety of medical contexts including cardiac disease, endocrine disorders, and hypovolemia, and in patients taking medications such as antihypertensive drugs, dopaminergic medication, and CNS depressants. Thus, detailed investigation may be necessary to clarify the cause of the postural hypotension, including other tests of autonomic function such as the response to the Valsalva maneuver.
Isometric Exercise
Sustained handgrip increases heart rate and blood pressure, partly by central command and partly by changes in contracting muscles that activate fibers subserving the afferent limb of the reflex arc.
The semirecumbent subject is required to maintain a pressure of 30 percent of maximal handgrip pressure for 5 minutes. The change in diastolic blood pressure is defined as the difference between the last value recorded before release of handgrip pressure and the mean resting value over the 3 minutes of recording preceding the isometric exercise. An increase in diastolic pressure of at least 15 mmHg is normal and is not dependent on age. The test is not used widely, however, because the results are not as reproducible as the response to postural change.
Cutaneous Vasomotor Control
Cutaneous blood flow is altered by stimuli such as a sudden inspiratory gasp, mental stress, startle, or alteration in temperature of another part of the body. Such changes in blood flow can be examined by plethysmography or laser Doppler velocimetry, as illustrated in Figure 21-7 . In normal subjects, an inspiratory gasp leads to a digital vasoconstriction through a spinal or brainstem reflex. The response is lost in the presence of a cord lesion or dysfunction of sympathetic efferent fibers to the digit under study, such as in patients with a polyneuropathy or entrapment neuropathy. A cold stimulus to the opposite hand, such as water at 4°C, similarly leads to reflex vasoconstriction. The digital vasoconstriction that occurs in response to mental stress (e.g., performing mental arithmetic despite distraction, or startle from a sudden loud noise) causes a transient increase in sympathetic vasomotor activity and thus evaluates sympathetic efferent pathways directly. Normal subjects sometimes have no response, however, leading to false-positive results.
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