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Clinical autonomic disease and the role of autonomic testing

By John C. Oakley, M.D., Ph.D

The autonomic nervous system (ANS) is responsible for the homeostatic control of numerous bodily functions such as blood pressure and body temperature regulation, urinary function, pupil size, sweating, sexual function, and digestion. Diseases of the ANS result in a complicated set of obvious and more subtle clinical signs and symptoms involving many different organ systems. Obvious clinical manifestations include orthostatic intolerance and syncope, abnormal sweating, constipation and diarrhea, incontinence, sexual dysfunction, and dry eyes and mouth. However, ANS dysfunction can also lead to less obvious symptoms such as fatigue, problems with visual accommodation, and heat intolerance.

The clinical approach to any autonomic disorder starts with a detailed history and physical examination. Sometimes this is sufficient to adequately diagnose and manage the patient. However, laboratory testing is often required to confirm the presence of ANS disease and to determine the location and distribution of the dysfunction. Patterns of ANS failure correlate with specific diseases. Many are potentially treatable and warrant further investigation when possible.

At the University of Washington Medical Center, we have developed an autonomic nervous system laboratory to perform a series of well-characterized, well-validated tests of autonomic function. The goals of ANS testing are to: 1) objectively determine the presence or absence of ANS disease, 2) quantify the severity of ANS dysfunction, 3) determine the distribution of dysfunction (i.e., central versus peripheral, sympathetic versus parasympathetic, or both), and 3) improve differential diagnosis and treatment.

Anatomy of the autonomic nervous system

The ANS is divided into two seemingly opposing systems — the sympathetic (SNS) and the parasympathetic (PNS) nervous systems — that act in concert at each target organ. The PNS conserves and replenishes energy stores and maintains homeostasis (rest-and-digest), while the SNS prepares the body for emergencies and increased muscle activity (fight-or-flight). Each system contains afferent and efferent connections and central and peripheral components connected by multiple synapses that use a variety of different neurotransmitters. ANS tests are divided into three main categories: those that measure PNS function, those that measure SNS sudomotor function, and those that measure SNS vasomotor function.

Parasympathetic Testing

PNS function is assessed by measuring baroreflex control of heart rate during maneuvers that modify blood pressure. The baroreflex is important in the homeostatic regulation of blood pressure. This control is mediated in part by rapid changes in heart rate in response to fluctuations in blood pressure. Mechanosensors in the carotid sinus and aortic arch send pressure-related information via cranial nerves IX and X to the brainstem nucleus tractus solitarius (NTS). Central integration of blood pressure occurs in the NTS and efferent output is sent via PNS to the heart (CN X) and via SNS to the heart and blood vessels. Thus, when blood pressure falls, as it does when the body is standing, the reduced pressure is sensed in the aortic arch and carotid sinus and induces changes in PNS and SNS outflow, which result in early increases in heart rate and later increases in peripheral vascular tone. These compensatory mechanisms act to resist the fall in blood pressure that occurs, for example, with standing. Early changes in heart rate are due exclusively to changes in PNS tone to the heart. Thus, early changes in heart rate in response to changes in blood pressure are a good measure of PNS function. Patients are asked to perform three different maneuvers that change blood pressure, and the heart rate response to each maneuver is measured.

The first test is metronomic breathing. The patient is asked to "breathe innn . . . " and "breathe outtt . . . " by the technologist at a steady rate of six breaths per minute (Figure 1).
metronomic breathing
Fig. 1
Metronomic breathing. The patient is asked to breathe deeply at six breaths per minute (bottom trace). Breathing is associated with regular fluctuations in blood pressure and heart rate.
This maneuver results in a slowly fluctuating blood pressure that decreases with inhalation and increases with exhalation due to changes in intrathoracic pressure. These blood pressure changes result in heart rate fluctuation via the baroreflex. The maximum heart rate variation between inhalation and exhalation and the ratio of heart rate during exhalation to that during inhalation (E:I ratio) are measured. Advantages of this test are its simplicity, reproducibility, and sensitivity to PNS dysfunction. The disadvantages are that the heart must be in sinus rhythm, the test is effort-dependent and thus requires patient cooperation, and multiple factors can affect the result, including medications, hypocapnia, position of the subject, and obesity. Test results are abnormal in autonomic failure syndromes and peripheral neuropathies involving the ANS. In particular, this test has a high sensitivity to autonomic dysfunction in diabetic patients, detecting problems even before obvious symptoms occur.

In the second test, the patient is asked to perform a Valsalva maneuver for 15 seconds (Figure 2). This results in a stereotyped fluctuation in blood pressure. Initially, there is a transient increase in BP due to increased intrathoracic pressure (phase I).
Valsalva maneuver
Fig. 2
Valsalva maneuver. The patient is asked to perform a Valsalva for 15 seconds, resulting in stereotyped changes in blood pressure and heart rate. Phase I, IIearly, IIlate, III, and IV are labeled (see text).
This is followed by a steady decline in BP as cardiac return falls (phase II early). With a short delay, the fall in BP is opposed via a baroreflex-mediated increase in heart rate and peripheral vasomotor tone. These compensatory mechanisms halt the fall in BP and eventually begin to increase the BP back towards baseline (phase II late). With release of the Valsalva there is a transient decrease in BP caused by decreased intrathoracic pressure during inhalation (phase III). The cardiac output rapidly returns to baseline. However, the peripheral vasomotor tone remains elevated, resulting in a transient overshoot in BP following the Valsalva maneuver (phase IV). The fast heart rate during the maneuver is caused by near complete removal of PNS tone. The transient overshoot in blood pressure following the Valsalva (phase IV) leads to a baroreflex-mediated suppression of heart rate. PNS function is measured by evaluating the ratio of the fastest heart rate during the maneuver to the slowest heart rate following the maneuver. This testing is sensitive, reproducible, quantitative, and simple. However, it is dependent on patient cooperation and requires that the heart be in sinus rhythm. The test returns abnormal results in the presence of both central and peripheral causes of autonomic dysfunction.

Stand-up test
Fig. 3
Stand-up test. Standing results in a transient decline in blood pressure with subsequent recovery and slight overshoot. The heart rate is measured at the 15th and 30th beats (lower trace).
The third test of baroreflex function is the stand-up test (Figure 3). The patient is asked to stand up as rapidly as possible from a lying position. This results in a transient decline in blood pressure followed by a brief overshoot in blood pressure. The initial fall in blood pressure causes a baroreflex-mediated increase in heart rate, which peaks at approximately the 15th beat after standing. The subsequent overshoot in blood pressure results in a baroreflex-mediated suppression of heart rate, which is maximal at approximately the 30th beat following standing. PNS function is measured by taking a ratio of the heart rate at the 30th beat to that at the 15th beat. This test is simple, quantitative, and clinically relevant. However, some patients may not be able to cooperate with this test. This test returns abnormal results in patients with central and peripheral autonomic dysfunction. Results are also abnormal in patients with postural orthostatic tachycardia syndrome (POTS) and baroreflex failure.

Sympathetic Vasomotor and Sudomotor Testing

Two components of SNS function are routinely measured in the autonomic laboratory. Vasomotor function is measured by evaluating the blood pressure response to the maneuvers described above — the metronomic breathing, Valsalva, and stand-up tests — and to a heads-up tilt table test. Sudomotor function is measured by quantitative sudomotor axon reflex testing (QSART), thermoregulatory sweat testing (TST), or sympathetic skin response (SSR). Tilt table testing is the most common test of SNS vasomotor function. After lying flat for 20 minutes, patients are tilted to at least 70 degrees, heads up. The blood pressure and heart rate responses are measured. An initial fall in blood pressure with recovery within tens of seconds is expected. Orthostatic hypotension is defined as a fall in blood pressure of greater than 20 mmHg systolic and/or 10 mmHg diastolic within the first 3 minutes. If the blood pressure falls below this level after 3 minutes, this is referred to as delayed orthostatic hypotension. Inability to maintain blood pressure with upright posture is associated with sympathetic vasomotor dysfunction. This test returns abnormal results in both peripheral and central autonomic failure syndromes. Tilt table testing can also be helpful in the diagnosis of postural orthostatic tachycardia syndrome and baroreflex failure.

The blood pressure response to standing is a measure of SNS vasomotor function. Standing results in an initial transient fall in blood pressure (Figure 3) followed within tens of seconds by an overshoot in blood pressure. Failure to maintain blood pressure with standing is associated with SNS vasomotor dysfunction either centrally or peripherally. This test is simple, clinically relevant, and quantitative. However, some patients may not be able to cooperate with standing.

The blood pressure response to the Valsalva maneuver is also a measure of SNS vasomotor function (Figure 2). During phase II of the Valsalva maneuver, which is described above, there is an initial transient fall in blood pressure due to decreased cardiac return followed by a recovery of blood pressure as baroreflex-mediated changes in heart rate and vasomotor tone occur. Patients with vasomotor dysfunction will have incomplete recovery of blood pressure during phase II. During phase IV of the Valsalva, an overshoot in blood pressure is expected, as cardiac output increases and peripheral vasomotor tone remains elevated. Lack of phase IV blood pressure overshoot is also an indication of SNS vasomotor dysfunction. Test results are abnormal in both central and peripheral SNS dysfunction. This test is simple, quantitative, reproducible, and sensitive to SNS disease, but it is dependent upon patient cooperation.

SNS sudomotor function is best measured with QSART. In this study, the rate of sweating is measured at baseline and after application of a cholinergic agonist. This test can help differentiate between central and peripheral ANS dysfunction. The test has a high sensitivity to small fiber involvement in neuropathy and in some cases may be the only objective evidence of small fiber neuropathy available.

An alternative measurement of SNS sudomotor function is the sympathetic skin response (SSR). A sweating response is seen after any unexpected, intense stimulus. In most labs, a brief forearm shock is applied, and the sweating response is measured in the hands and in the feet. The SSR involves both central and peripheral components of the SNS and thus cannot localize the site of dysfunction, but it does provide additional useful information about SNS function.

Routine evaluation of ANS dysfunction is now available at the University of Washington and can be scheduled by calling (206) 598-4211. Our goal is to assist in the diagnosis and management of patients with ANS disease. In doing so, we hope to increase awareness of ANS disease in the community.

Indications for Laboratory Evaluation
To set up a laboratory evaluation, call (206) 598-4211.

  • Diagnosis of generalized autonomic failure
  • Diagnosis of benign autonomic disorders
  • Diagnosis of distal small fiber neuropathy
  • Evaluation of orthostatic intolerance
  • Evaluation for autonomic dysfunction in known peripheral neuropathies
  • Detection of sympathetic dysfunction in sympathetically mediated pain syndromes