Electrodiagnostic Studies of the Autonomic Nervous System

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, NewYork-Presbyterian Hospital, Cornell Campus. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Pfizer and Merck.

Source: Hilz MJ, Dutsch M. Quantitative Studies of Autonomic Function. Muscle Nerve. 2006;33:6-20.

Clinical testing of the autonomic nervous system (ANS), primarily focusing on sudomotor and cardiovascular function, is useful in the diagnosis of autonomic disorders of the peripheral or central nervous system, and comprises generally available tests including the sympathetic skin response and heart-rate variability at rest, during deep breathing, standing, and the Valsalva maneuver. More advanced study of the ANS is predominantly of research interest, and includes spectral analysis of heart rate and blood pressure modulation, baroreflex testing, measurement of sweat production, quantitative sudomotor axon reflex testing, and microneurography. Together, these studies allow for thorough assessment of sympathetic and parasympathetic function.

Cardiovascular autonomic function is best challenged using the Valsalva maneuver, active standing, and metronomic breathing. During the Valsalva maneuver, the patient, using a special mouthpiece, maintains an expiratory pressure of 40 mmHg for 15-20 seconds. Phase 1, the first 2-3 seconds, demonstrates decreased heart rate and increased blood pressure due to mechanical pressure on the aorta. Phase 2 comprises an initial dip in blood pressure due to decreased venous return consequent to the continuous expiratory strain, activating the baroreflex, increasing peripheral vascular resistance, and consequently blood pressure. Phase 3, encompassing the first 1-2 seconds following release of the expiratory strain, exhibits passive increase in heart rate and drop in blood pressure, followed by phase 4, overshooting of blood pressure consequent to the continued increased peripheral vascular resistance, with baroreflex-induced bradycardia. The Valsalva ratio, the highest heart rate on expiration vs the lowest heart rate following release of the expiratory strain, primarily analyzes parasympathetic heart-rate control, and a value < 1.10 is abnormal.

Deep metronomic breathing at 6 cycles per minute maximally induces heart rate variability, and the difference between maximum to minimum heart rate during respiration is the best measure of sinus arrhythmia consequent to parasympathetic cardiac influences. Values less than 5 beats/min are abnormal in the over 50-year-old population.

Despite contraction of leg and abdominal muscles with enhanced venous return and increased cardiac output in the upright position, active standing results in an overall drop in peripheral vascular resistance and an initial drop in blood pressure, depressing parasympathetic outflow, enhancing sympathetic activity, resulting in secondary tachycardia and recovery, even overshoot, of blood pressure within 7 seconds. By consensus of the American Autonomic Society and American Academy of Neurology, systolic blood pressure drops of > 20 mm Hg or diastolic > 10 mm Hg within 3 min. of active standing satisfy criteria for orthostatic hypotension. Head-up tilting permits prolonged, 5-10 min, orthostatic stress, resulting in initial blood pressure drop, baroreflex activation, inhibition of cardiovagal outflow, increased sympathetic activity, tachycardia, and blood pressure increase.

Sustained hand-grip, the cold pressor test (immersion of an arm in ice water), and the cold face test (application of cold compresses to the forehead and maxillary region) are autonomic challenge maneuvers for the sympathetic (former 2) or sympathetic and parasympathetic nervous system (cold face test), but are unpleasant (cold pressor test) or lack reproducibility (sustained hand-grip).

Sudomotor function may be studied using the thermoregulatory sweat test (TST), the quantitative sudomotor axon reflex test (QSART), and the sympathetic skin response (SSR). For the TST, subjects are totally enclosed in a sweat cabinet for 45-65 min. at 45-50°C, lying supine, unclothed, on a cart with the exposed body surface (exclusive of eyes, nose, mouth, genitalia) covered with indicator powder (alizarin red, sodium carbonate, and cornstarch), which changes color with perspiration. Perspiration is provoked by a rise in core temperature generated by raising the ambient temperature, generating an efferent sympathetic response mediated by preganglionic centers, including the hypothalamus, bulbospinal pathways, intermediolateral cell columns, and white rami communicans, and by postganglionic pathways, including the sympathetic chain and postganglionic sudomotor nerves. Skin temperature is maintained at 39-40°C via overhead infrared heaters. Appropriate skin temperature is critical to recruiting a maximal central response and to avoid skin injury or direct sweat gland activation. Sweat distribution is documented by digital photography of the body surface, and normal persons demonstrate relatively uniform sweating over the body with characteristic areas of heavier or lighter sweating.

Innervation of eccrine sweat glands is primarily mediated through postganglionic cholinergic sympathetic fibers. Acetylcholine, when iontophoresed into skin, directly stimulates sweat glands, concomitantly generating a antidromic response in sympathetic fibers which spread to a branch point, and orthodromically to nearby sweat glands, the output of which is measured by a sudorometer in the QSART. QSART is sensitive and reproducible in controls and neuropathy patients, and recordings are symmetrical in normals. Reduced or absent sweat responses indicate postganglionic sympathetic sudomotor failure

Sympathetic skin responses (SSRs) do not directly measure sudomotor activity. Rather, SSRs measure a skin potential generated by an alteration in skin conductivity produced by sweat production. SSRs are not sensitive, results are variable, and responses tend to habituate. Despite general agreement that loss of the SSR is abnormal, controversy exists whether reduction in amplitude and latency change are reliable abnormalities. Results must be interpreted with caution.

Microneurography directly records efferent muscle sympathetic nerve activity, reflecting intramuscular vascular vasoconstriction, but is invasive and time-consuming, making it a research, rather than a clinical, tool.

Commentary

Autonomic cardiovascular function may also be evaluated by a recently described test, which is both safe and simple to perform. Administration of a single breath of 35% CO2 stimulates the hypothalamic-pituitary-adrenal axis and, in normal subjects, activates vagal cardiac autonomic input, inducing bradycardia. Among 19 males, aged 18-70 years, with diabetes of at least 3 years duration, 11 demonstrated autonomic neuropathy based on abnormal R-R interval, expiration/inspiration ratio, and Valsalva index. Of the remaining 8 diabetics, 2 had peripheral neuropathy but none had autonomic neuropathy. Thirty-five percent CO2 failed to induce bradycardia in the autonomic neuropathy patients, but did evoke the expected response in the non-neuropathy group (P < 0.0001). All patients tolerated the procedure well without significant adverse effects. The 35% CO2 challenge test is a useful adjunct in the evaluation of autonomic neuropathy.