The wheal and the deeply colored red areola are caused by the direct action of histamine on blood vessels in response to local injury, while the flare depends on the integrity of the axon reflex. This axon reflex is mediated by antidromic stimulation of small sensory C fibers that results in the release by the same fibers of various vasoactive substances such as bradykinin and substance P. Destruction of the dorsal root ganglion, but not the dorsal root, eliminates the flare. The flare component is influenced centrally through a yet unknown mechanism. In familial dysautonomia, the flare response to histamine and to scratch is absent. It may also be absent in peripheral neuropathies that involve sympathetic nerves (e.g., diabetes, alcoholic–nutritional disease, Guillain-Barré disease, amyloidosis, porphyria). The quantitative sudomotor response to topical acetylcholine, described earlier, is preferred for its sensitivity and accuracy but requires special equipment.
The dermatographic wheal and flare response may be lost below the level of a recent cord injury but returns over days or longer, comparable to recovery from spinal shock.
While these are not parts of the routine laboratory evaluation of autonomic nervous system disease, they nonetheless present interesting physiologic information. The infusion of NE causes a rise in blood pressure, which is usually more pronounced for a given infusion rate in dysautonomic states than it is with normal subjects. In many instances, for example, the Guillain-Barré syndrome, the excessive rise in blood pressure is thought to be more a result of inadequate muting of the hypertension by baroreceptors than it is a reflection of true denervation hypersensitivity, that is, it reflects dysfunction of the afferent limb of the reflex arc. In patients with familial dysautonomia, the infusion of NE produces erythematous blotching of the skin, like that which may occur under emotional stress, probably representing an exaggerated response to endogenous NE.
The infusion of angiotensin II into patients with idiopathic orthostatic hypotension also causes an exaggerated blood pressure response. A similar response to methacholine and NE has been interpreted as a denervation hypersensitivity to neurotransmitter or related substances. A different mechanism must be invoked for the blood pressure response induced by angiotensin; perhaps it is caused by a defective baroreceptor function.
The integrity of autonomic innervation of the heart can be evaluated by the intramuscular injection of atropine, ephedrine, or neostigmine while the heart rate is monitored. Normally, the intramuscular injection of 0.8 mg of atropine causes tachycardia as a result of a parasympathetic block and a withdrawal of vagal tone. No such change occurs in cases of parasympathetic (vagal) denervation of the heart, the most common such conditions being diabetes and the Guillain-Barré syndrome and the most dramatic being the brain death state, in which there is no longer any tonic vagal activity to be ablated by atropine.
Laboratory methods are available for the measurement of NE and dopamine b-hydroxylase in the serum. Normally, when a person changes from a recumbent to a standing position, the serum NE level rises twoor threefold. In patients with central and peripheral autonomic failure, there is little or no elevation on standing or with exercise. The dopamine b-hydroxylase enzyme is deficient in patients with a rare form of sympathetic dysautonomia.
In summary, the noninvasive tests listed in Table 25-1 and described earlier are quite adequate for the clinical testing of autonomic function. Low has emphasized that the most informative tests are those that are quantitative and have been standardized and validated in patients with both mild and severe autonomic disturbances.