Clinical Vignette

A 65-year-old man presented with subacute onset of severe unexplained orthostatic dizziness and light-headedness. Over the next 2 months, he developed dry mouth, dry eyes, urinary hesitancy, erectile dysfunction, and severe constipation. His previous medical history was unremarkable. His only medication was aspirin. He smoked one pack per day and drank sparingly. His family history was noncontributory. The patient’s blood pressure was 124/76 mm Hg supine and 66/40 mm Hg standing at 2 minutes, with normal heart rates of 72 and 76 beats per minute while supine and standing. His remaining general examination was normal. There were impaired pupillary responses to light and accommodation and dry mucous membranes. Sensory examination revealed distal sensory loss to proprioception in both hands and feet.

Tilt-table testing revealed orthostatic hypotension. Sweat testing demonstrated profound anhidrosis. Paraneoplastic autoantibody studies revealed positive anti-HU (antineuronal) antibodies. Chest computed tomography demonstrated left hilar mass. Small-cell lung carcinoma was diagnosed after bronchoscopic biopsy. The patient’s orthostatic intolerance improved after the third course of chemotherapy. Remission has persisted.

Comment: Development of signs and symptoms related to parasympathetic and sympathetic dysfunction in the absence of central nervous system abnormalities was compatible with an autonomic neuropathy.

Anatomy of the Autonomic System

The primary role of the autonomic system is the maintenance of homeostasis and this is done by two separate but complementary systems: the sympathetic and the parasympathetic systems. The central regulation of the autonomic system is mediated by neurons in the frontal lobe, limbic system and the hypothalamus. The preganglionic neurons of the sympathetic nervous system arise from the intermediolateral column of the thoracic spinal cord. These axons form the white communicating rami that synapse with the neurons of the sympathetic ganglia in the paravertebral chain; postganglionic fibers form the gray communicating rami that travel along with the spinal nerves to blood vessels and sweat glands (Fig. 13-1). Sympathetic innervation of the adrenal medulla is the exception as it receives preganglionic sympathetic fibers; the adrenal medulla is considered the equivalent of a sympathetic ganglion, and it secretes epinephrine and norepinephrine directly into the blood stream (Fig. 13-1).

Figure 13-1 Cholinergic (C) and Adrenergic (A) Synapses: Schema.

The parasympathetic system consists of the cranial and sacral output; the cranial output arises in the visceral nuclei of the cranial nerves III, VII, IX, and X, and the axons travel along with the respective cranial nerves to innervate target organs. The preganglionic fibers from the Edinger–Westphal nucleus travel in the oculomotor nerve (III) and synapse in the ciliary ganglion innervating the ciliary and pupillary muscles (Fig. 13-2). The preganglionic fibers from the superior salivatory nuclei travel along with the facial nerve (VII) as greater petrosal nerve and the chorda tympani, synapse in the sphenopalatine and submandibular ganglion, and innervate the lacrimal, submandibular, and sublingual glands (Fig. 13-3). The preganglionic fibers from the inferior salivatory nuclei travel along with the glossopharyngeal nerve (IX) and synapse in the otic ganglion and innervate the parotid gland (Fig. 13-4). The preganglionic fibers from the dorsal motor nucleus of the vagus travel along with the vagal nerve (X) and synapse in the ganglia in the walls of the viscera and innervate the visceral organs of the gastrointestinal, cardiac, and renal systems (Fig. 13-5). The sacral part of the parasympathetic system arises from the sacral spinal cord, synapses in the ganglia in the walls of the organs, and innervates the colon, bladder, and pelvic organs (Fig. 13-6).

Figure 13-2 Eye: Autonomic Innervation.

Figure 13-3 Facial Nerve: Autonomic Innervation.

Figure 13-4 Glossopharyngeal Nerve: Autonomic Innervation.

Figure 13-5 Vagus nerve: Autonomic Innervation.

Figure 13-6 Pelvic Organs: Autonomic Innervation.

Autonomic functions are mediated through neurotransmitters released by the sympathetic and parasympathetic neurons. Acetylcholine is the most important neurotransmitter. This is released by preganglionic sympathetic and parasympathetic neurons as well as all postganglionic parasympathetic neurons and some postganglionic sympathetic neurons (e.g., sweat glands). Norepinephrine is the other important autonomic neurotransmitter. It is secreted by the remaining postganglionic sympathetic neurons directing its action on both α- and β-adrenergic receptors.

Diagnostic Approach

Patients with dysautonomic symptoms require careful, and complete, neurologic examinations to find concomitant features of central and peripheral nervous system involvement. Electromyography is often valuable in patients who have concomitant sensorimotor neuropathy findings. Heart rate responses to Valsalva maneuvers and deep breathing are used to assess cardiovagal parasympathetic function.

Commonly used parameters to assess sympathetic competency include blood pressure responses to standing and to Valsalva maneuvers and quantitative measurements of sweat production in response to cholinergic stimuli. The latter is typically done at four standardized locations to detect the abnormality pattern. Quantitative sensory testing, comparing thresholds for vibration to cold- and heat-pain thresholds, is helpful for detecting small myelinated and unmyelinated somatic peripheral nerve dysfunction. Quantitation of intraepidermal nerve fiber density by skin punch biopsy and subsequent immunostaining directed at axons is performed at some centers to assess the severity of small-fiber loss. Comprehensive screening for all recognized paraneoplastic antibodies is recommended in acute to subacute cases where paraneoplastic autonomic neuropathy is possible.

Clinical Presentations

Typically, patients have combinations of both parasympathetic and sympathetic dysfunction (Fig. 13-7). The former is characterized by dry mucous membranes, particularly noticeable in the eyes and mouth, with varying gastrointestinal involvement manifested as early satiety, nausea, vomiting, constipation, diarrhea, urinary bladder dysmotility, and erectile dysfunction.

Figure 13-7 Symptoms of Dysautonomia.