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.

Disorders of sweating and sudden feelings of severe light-headedness or syncope when assuming an upright posture are usual symptoms of impaired sympathetic function. Combinations of parasympathetic (erection) and sympathetic (ejaculation) disorders affect sexual function. Signs of autonomic dysfunction include fixed heart rates, tonic pupils, and orthostatic hypotension, with normal strength and sensory examination (i.e., sparing the somatic nerves). Autonomic disorders may be classified as peripheral or central autonomic disorders and may present acutely or in a chronic fashion.

Therapy

Primary treatment consists of specific therapies for the underlying disorders, when these are identified and, when possible, symptomatic relief per se. Nonpharmacologic treatments of orthostatic hypotension include increasing intake of dietary salt and water, eating smaller and more frequent meals, avoiding alcohol, and wearing elastic stockings or abdominal binders. Medications include sympathetic agents such as midodrine and fluid- and salt-conserving agents such as fludrocortisone. Orthostatic symptoms typically seen in POTS may respond to low-dose β-blockers or low-dose midodrine.

Bladder dysfunction in most dysautonomic conditions is characterized by failure to empty. Treatments include timed voiding, intermittent catheterizations, and, rarely, indwelling catheters. Pharmacologic agents that promote bladder emptying, such as bethanechol, have limited efficacy. Bladder pacemakers and botulinum toxin injections may benefit select patients.

Treatment of erectile dysfunction includes agents such as sildenafil, yohimbine, topical nitroglycerin or minoxidil, injections of prostaglandins, or penile implants.

Gastrointestinal dysfunction is best aided by strategies to maintain hydration and nutrition. Gastroparesis is treated with prokinetic agents such as metoclopramide; constipation is treated with increased fiber intake and laxatives.

Plasma exchange and intravenous immunoglobulin are used for the treatment of suspected immune-mediated autonomic neuropathy with variable success.

Prognosis

This depends on the etiology, severity, and overall degree of autonomic dysfunction. Autoimmune autonomic neuropathies often have a limited, unsatisfactory improvement. Patients with Guillain–Barré syndrome usually experience complete resolution of autonomic dysfunction in parallel with clinical recovery of strength. Prognosis for chronic peripheral and central autonomic disorders is less favorable.

Syncope

Clinical Vignette

A 24-year-old man was at work on his first day as a laboratory technical assistant. He was assisting the phlebotomist with a difficult blood draw when he went pale and sweaty and fell to the ground. There was no tonic–clonic activity, tongue biting, or urinary incontinence. He came around and was alert in just a few seconds. His only symptom when he came around was “embarrassment.” His general physical examination including blood pressure and pulse and neurologic examination was normal.

Syncope is defined as a brief and transient loss of consciousness from cerebral hypoperfusion. Lightheadedness, visual dimming, paleness, cold sweating, nausea, and a feeling of warmth are common premonitory symptoms (Fig. 13-8). These are followed by loss of consciousness and postural muscle tone, and, if the patient is standing, he or she will usually fall. Significant trauma and fractures occur in approximately 5% of these patients. In contrast to patients who lose consciousness from a convulsion, individuals who have syncope generally have no confusion after the episode. Typically, they have good recollection of premonitory symptoms. Loss of consciousness lasts just a few seconds. Occasionally, a few clonic twitches or a brief generalized seizure-like activity occurs at the end of the episode. EEG recorded during syncope demonstrates early depression of activity followed by slow wave activity in the theta and delta range. Transient EEG voltage depression may follow. Elderly patients may be amnestic for the event. Almost 20% of people have had a syncopal episode in their lifetime.

Figure 13-8 Syncope: Four-Step Management Approach.

Syncope may be classified as having cardiac or noncardiac origin. Cardiac syncope may be due to cardiac disease (arrhythmias or valvular disease) or may be cardiac reflex syncope from orthostatic hypotension. Noncardiac syncope is subclassified as neurologic, metabolic, or idiopathic.

The most common type, cardiac reflex syncope, has three subtypes: vasovagal (called neurocardiogenic or vasodepressor), situational (e.g., micturition, Valsalva, ocular compression, venipuncture, fear, exertion), and carotid hypersensitivity.

Vasovagal cardiac reflex syncope is the most commonly seen syncope in neurologic practice. Its pathophysiology is unresolved. The reflex is initiated by an intense sympathetic activation (e.g., a painful stimulus or fear) with increase of blood pressure, tachycardia, decreased cardiac filling (“empty heart”), and powerful cardiac contractions that stimulate heart mechanoreceptors. Subsequently, cardiac inhibitor pathway activation causes a short-term increase of vagal activity and withdrawal of sympathetic activity, known as the Bezold–Jarisch reflex. The loss of consciousness, secondary to cerebral hypoperfusion, is primarily from a combination of profound bradycardia and arterial pressure collapse. Vasovagal syncope often occurs while assuming the upright posture. In these instances, diminished blood return from the lower limbs and viscera and a subsequent pooling of blood in the lower body result in decreased cardiac filling and initiation of the cascade of events.

Orthostatic hypotension is another common cause of syncope. A tilt-table test is essential to the evaluation of these patients and in the investigation of syncope of unclear origin. The causes of orthostatic hypotension vary and merit further evaluation. Medications of many classes are common causes of hypotension leading to syncope. Dehydration and hypovolemia are other, easily excluded, common pathophysiologic mechanisms. Hyperventilation with associated hypocapnia is a rare cause of syncope. Metabolic causes of syncope include hypoglycemia and hypoxia. Psychogenic syncope sometimes can be difficult to document. It is best excluded by a careful history, witnessing the event, or both.

Primary neurologic causes of syncope are uncommon and usually have other associated symptoms. Peripheral neuropathies are the most common neurologic causes of syncope associated with orthostatic hypotension, particularly in patients with neuropathies secondary to diabetes and rarely primary amyloidosis. Central nervous system disorders such as multiple system atrophy with parkinsonian, cerebellar, or mixed features, previously called Shy–Drager disease, and pure autonomic failure must be considered despite their rare occurrence. Transient ischemic attacks in the vertebrobasilar system or basilar migraine are conditions that rarely produce syncopal episodes. There is no evidence that unilateral or bilateral critical carotid stenosis can cause syncope. The drop attacks of epileptic seizures are infrequently confused with syncope; although these patients lose postural tone and “drop,” they do not lose consciousness.

The clinical examination of a patient with presumed syncope aims first to exclude serious illnesses, including structural heart disease, such as valvular aortic stenosis, cardiac rhythm disturbances, such as brady arrhythmias, coronary artery disease, and cardiomyopathies with compromised cardiac output. Patients with syncope from heart disease have a higher mortality rate than individuals with other causes of syncope. Evaluation must include a detailed history and physical examination with particular attention to the heart, an ECG, Holter monitor, other forms of cardiac event monitoring, echocardiography, stress test, and occasionally invasive electrophysiologic testing. Autonomic testing including quantitative sweat testing, heart rate responses to deep breathing and Valsalva maneuver and tilt-table tests are indicated in patients where autonomic dysfunction is suspected.

The management of syncope focuses on the underlying disease process, often requiring specialized medical or surgical treatments. Cardiac, neurologic, and situational mechanisms must be addressed. The therapy of reflex vasovagal syncope is problematic. Analysis of whether syncope is primarily from cardiac inhibition or hypotension is sometimes difficult because these often occur together. Education, increased salt and fluid intake, β-blockers, blood volume expanders such as mineralocorticoids (fludrocortisone), α-adrenergic agonists such as midodrine, and serotonin reuptake inhibitors are recommended. Antiarrhythmic agents and pacemakers are also sometimes indicated.