Autonomic neuropathies and gastroparesis

Autonomic reflex tests

Autonomic reflex tests using sensitive and reproducible measurements have been used at more medical centers as a feasible and reliable neurophysiological diagnostic tool in the United States. Autonomic reflex tests have improved diagnosis process for autonomic neuropathies and largely evaluate cardiovascular and sudomotor autonomic reflexes. The two autonomic systems have a few advantages over other systems. Neuronal pathways relevant to the autonomic reflex tests have been relatively well studied in human and animal models. Hemodynamic parameters and sweat measures can be monitored continuously and easily quantified. The tests can be performed as an outpatient basis through non-invasive methods without sedation of patients.

Cardiovascular assessment in the autonomic reflex test consists of evaluation for cardiovagal function, sympathetic adrenergic function, and hemodynamic response to orthostatic stress. Cardiovagal function can be evaluated by analyzing heart rate changes to various stimuli. For a beat-to-beat heart rate monitoring, intervals between two neighboring R waves of QRS complexes on a continuous electrocardiogram are recorded with each heartbeat. Common stimuli to induce cardiovagal activities are deep breathing, Valsalva maneuver, and active standing. Deep and slow breaths at 5–6 times per minute maximize changes in heart rates or heart rate variability. Inspiration increases heart rate through vagal tone withdrawal and expiration decreases heart rate with vagal activation ( Fig. 10.1A ). The exact mechanism of the cardiovagal activities to the breathing cycles is largely unknown in humans although stretch receptors in the chest wall (Hering-Breuer reflex) and cardiac stretch receptors (Bainbridge reflex) play important roles in animals. It is believed that the breathing frequency at 5–6 breaths per minute create a maximum synchrony in the cardiovagal neurons in the brainstem resulting in the highest heart rate variability. There are various methods to measure heart rate changes. And patient’s heart range change is compared to age-specific normative data. A Valsalva maneuver produces dynamic changes in blood pressure and heart rate secondary to cardiovagal and sympathetic activities. Valsalva ratio, which reflects how rapidly heart rate drops following discontinuation of the Valsalva maneuver, is another measure of cardiovagal function. It will discussed later with sympathetic adrenergic measures. A 30:15 ratio (of heart rate) to an active standing is a third measure for cardiovagal function. With an active standing from a supine position, there is an acute shift in blood volume due to gravity and exercising muscle that draw in blood. Heart rate increases rapidly as a compensatory mechanism in order to minimize blood pressure drop secondary to the shift, then decreases with recovery of blood pressure . Heart rate reaches its peak at approximately 12 s after standing up. A 30:15 ratio is obtained by dividing an increased heart rate at 15 s after standing by a decreased heart rate at 30 s. It is also estimated by measuring a 15th RR interval and a 30th RR interval. However, because time to a peak heart rate can be different between healthy subjects and patients , a ratio of an absolute maximum to a minimum heart rate after standing can be used and increases sensitivity.

Sympathetic adrenergic function is assessed by recording beat-to-beat blood pressure in response to a Valsalva maneuver, active standing and passive standing on a tilt-table. With a volume clamped method of Peňáz, arterial blood pressure can be measured in a non-invasive and continuous way. For a Valsalva maneuver, a subject is asked to blow through a closed tube at expiratory pressure of 40 mmHg for 15 s. Blood pressure waveform during a Valsalva maneuver has four distinct phases ( Fig. 10.1D ). With the Valsalva maneuver, the glottis is closed and the subject breathes against the closed glottis causing a forced expiration and increased intrathoracic pressure. Its mechanical effect directly from the high intrathoracic pressure increases blood pressure during phase I. During phase II, the high intrathoracic pressure reduces venous return to the heart resulting in decreasing cardiac output and dropping blood pressure (early phase II). The dropping blood pressure is sensed by the baroreceptors in the carotid sinus, the great vessel and the right atrium triggering baroreflex. The efferent pathways of baroreflex work through cardiovagal withdrawal and sympathetic activation to the heart and the blood vessels. Peripheral α-adrenergic activation on the vasculatures constrict peripheral vasculature. It is the main mechanism that recovers blood pressure during late phase II. Right upon discontinuation of the forced expiration, there is a transient drop in blood pressure due to mechanical effects because the intrathoracic pressure becomes relatively negative abruptly (phase III). Heart rate starts to rise initially by vagal withdrawal and later mainly by β-adrenergic sympathetic cardiac activation during phase II and III. When the forced expiration is stopped, a large volume of venous blood returning to the heart is pumped out by the heart at the increased rate. This leads to excessively increased cardiac output and rapidly increasing blood pressure, also known as blood pressure ‘overshooting’ during phase IV. Therefore, β-adrenergic sympathetic activation contributes to overshooting. Recovery of blood pressure during late phase II and blood pressure overshooting during phase IV are markers of normal sympathetic adrenergic function. The blood pressure overshooting triggers baroreflex activating cardiovagal tone and drops heart rate rapidly. A Valsalva ratio, a cardiovagal measure, is calculated from a maximal heart rate during phase IV and a following minimal heart rate ( Fig. 10.1C ). Patient’s Valsalva ratio is compared to age and sex-specific normative data.

The quantitative sudomotor axon reflex test (QSART) is a method to evaluate the post-ganglionic sympathetic cholinergic pathway. A dual-chamber capsule is placed tightly on the skin at four standardized areas of limbs, usually three on the lower extremity and one on the upper. Solution with acetylcholine in an outer chamber of the capsule has direct contact with the skin within the air-tight seal. Acetylcholine is penetrated into the skin by iontophoresis and stimulates unmyelinated C-fibers innervating the sweat glands. Neuronal excitation on the stimulated axons spreads to neighboring axons by axon-to-axon reflex summoning more sweat glands. The sweat amount is estimated based on relative changes in humidity in an inner chamber of the capsule. QSWEAT is a commercialized version of QSART. QSART is designed to detect a length-dependent small-fiber neuropathy. Abnormal QSART findings that do not have a distal-dominant pattern need cautious clinical interpretation.

Thermoregulatory sweat test (TST)

TST is another sweat test that provides topographical information on loss of sweating. A patient remains in a supine position in a sweat chamber where a room temperature is maintained high with control of humidity in order to induce sweating. Powder mixture is spread over the front side of patient’s body. Relatively low pH of sweating changes the color of indicator in the powder mixture, either alizarin red or iodine. TST can be helpful in determining presence of extra-intestinal autonomic dysfunction, localizing sudomotor problems, determining severity of autonomic failure, and following progression of disease . Fig. 10.2 shows various patterns of sweating abnormalities in patients with different gastrointestinal problems seen at our autonomic clinic.

Skin biopsy

Skin biopsy is a pathological test for small-fiber neuropathies with relatively low risks to measure densities of mostly unmyelinated and thinly myelinated fibers in the epidermal layers of the skin. These fibers are mainly sensory nerve fibers. Bright-light immunohistochemistry protocol stains axons of the fibers with anti-protein gene product 9.5 antibody and makes them apparent under microscope as seen in Fig. 10.3 . Multiple sections from each skin sample are used to measure average intradermal nerve fiber densities . From the same samples of a skin biopsy, autonomic fibers innervating the sweat glands in the dermis can be evaluated and its methods for quantification have been improved by using computer software. New techniques reduce large variabilities originating from convoluted structure of the sweat glands . However, sweat gland nerve fiber density measurements through a skin biopsy have not been approved as a clinical diagnostic test for autonomic neuropathies yet although measurement of intraepidermal nerve fiber density is approved for clinical use. For research purpose, it is possible to assess autonomic innervation of other structures, such as blood vessels and arrector pili muscles, as well as to identify its neurochemical markers including tyrosine hydroxylase (sympathetic adrenergic fibers) and vasoactive intestinal peptide (sympathetic cholinergic fibers) .