Neurology_Adams

Neurology_Adams. Finally, there is the essential role that the hypothalamus plays in the initiation and regulation of autonomic activity, both sympathetic and parasympathetic. Sympathetic responses are most readily obtained by stimulation of the posterior and lateral regions of the hypothalamus, and parasympathetic responses from the anterior regions. The descending sympathetic fibers are largely or totally uncrossed. According to Carmel, fibers from the caudal hypothalamus at first run in the prerubral field, dorsal and slightly rostral to the red nucleus, and then ventral to the ventrolateral thalamic nuclei; then they descend in the lateral tegmentum of the midbrain, pons, and medulla to synapse in the intermediolateral cell column of the spinal cord. In the medulla, the descending sympathetic pathway is located in the posterolateral retroolivary area, where it is frequently involved in lateral medullary infarctions. In the cervical cord, the fibers run in the posterior angle of the anterior horn


Neurology_Adams

Neurology_Adams. is located in the posterolateral retroolivary area, where it is frequently involved in lateral medullary infarctions. In the cervical cord, the fibers run in the posterior angle of the anterior horn (Nathan and Smith). According to the latter authors, some of the fibers supplying sudomotor neurons run outside this area but also remain ipsilateral. Jansen and colleagues, by the use of viral vectors in rodents, were able to label certain neurons of the hypothalamus and the ventral medulla that stimulated sympathetic activity in both the stellate ganglion and the adrenal gland. They hypothesized that this dual control underlies the fight-or-flight response, as described in Chap. 24. By contrast, the pathways of descending parasympathetic fibers are not well defined.


Neurology_Adams

Neurology_Adams. Afferent projections from the spinal cord to the hypothalamus have been demonstrated in animals and provide a potential route by which sensation from somatic and possibly visceral structures may influence autonomic responses. The function of the autonomic nervous system in its regulation of the visceral organs is to a high degree independent of voluntary control and awareness. Furthermore, when the autonomic nerves are interrupted, these organs continue to function (the organism survives), but they are no longer as effective in maintaining homeostasis and adapting to the demands of changing internal conditions and external stresses.


Neurology_Adams

Neurology_Adams. Viscera have a double-nerve supply, sympathetic and parasympathetic and in general these two parts of the autonomic nervous system exert opposite effects. For example, the effects of the sympathetic nervous system on the heart are excitatory and those of the parasympathetic inhibitory. However, some structures—sweat glands, cutaneous blood vessels, and hair follicles—receive only sympathetic postganglionic fibers, and the adrenal gland, as indicated earlier, has only a preganglionic sympathetic innervation. Also, some parasympathetic neurons have been identified in sympathetic ganglia.


Neurology_Adams

Neurology_Adams. All autonomic functions are mediated through the release of chemical transmitters. The modern concept of neurohumoral transmission had its beginnings in the early decades of the twentieth century. In 1921, Loewi discovered that stimulation of the vagus nerve released a chemical substance (Vagusstoff) that slowed the heart. Later this substance was shown by Dale to be acetylcholine (ACh). Also, in 1920, Cannon reported that stimulation of the sympathetic trunk released an epinephrine-like substance, which increased the heart rate and blood pressure. He named this substance “sympathin,” subsequently shown to be norepinephrine, or NE. Dale found that ACh had pharmacologic effects similar to those obtained by stimulation of parasympathetic nerves; he designated these effects as “parasympathomimetic.” These observations placed neurochemical transmission on solid ground and laid the basis for the distinction between cholinergic and adrenergic transmission in the autonomic nervous system.


Neurology_Adams

Neurology_Adams. The most important of the autonomic neurotransmitters are ACh and NE. ACh is synthesized at the terminals of axons and stored in presynaptic vesicles until it is released by the arrival of nerve impulses. ACh is released at the terminals of all preganglionic fibers (in both the sympathetic and parasympathetic ganglia), as well as at the terminals of all postganglionic parasympathetic and a few special postganglionic sympathetic fibers, mainly those subserving sweat glands. Of course, ACh is also the chemical transmitter of nerve impulses to the skeletal muscle fibers. Parasympathetic postganglionic function is mediated by two distinct types of ACh receptors: nicotinic and muscarinic, so named by Dale because the choline-induced responses were similar either to those of nicotine or to those of the alkaloid, muscarine. The postganglionic parasympathetic receptors are located within the innervated organ and are muscarinic; that is, they are antagonized by atropinic drugs. As already


Neurology_Adams

Neurology_Adams. those of the alkaloid, muscarine. The postganglionic parasympathetic receptors are located within the innervated organ and are muscarinic; that is, they are antagonized by atropinic drugs. As already mentioned the receptors in ganglia, like those of skeletal muscle, are nicotinic; they are not blocked by atropine but are counteracted by other agents (e.g., tubocurarine).


Neurology_Adams

Neurology_Adams. It is likely that more than ACh is involved in nerve transmission at a ganglionic level. Many peptides— substance P, enkephalins, somatostatin, vasoactive intestinal peptide, adenosine triphosphate (ATP), and nitric oxide—have been identified in the autonomic ganglia, localizing in some cases to the same cell as ACh. (This negates “Dale’s principle,” or “law,” which stipulates that one neuron elaborates only one neurotransmitter, as outlined by Tansey.) Particular neuronal firing rates appear to cause the preferential release of one or another of these substances. Most of the neuropeptides exert their postsynaptic effects through the G-protein transduction system, which uses adenyl cyclase or phospholipase C as an intermediary. The neuropeptides act as modulators of neural transmission, although their exact function in many cases remains to be determined.


Neurology_Adams

Neurology_Adams. With two exceptions, postganglionic sympathetic fibers release only NE at their terminals. The sweat glands and some blood vessels in muscle are innervated by postganglionic sympathetic fibers, but their terminals, as mentioned, release ACh. The NE that is discharged into the synaptic space activates specific adrenergic receptors on the postsynaptic membrane of target cells.


Neurology_Adams

Neurology_Adams. Adrenergic receptors are of two types, classified originally by Ahlquist as alpha and beta. In general, the alpha receptors mediate vasoconstriction, relaxation of the gut, and dilatation of the pupil; beta receptors mediate vasodilatation, especially in muscles, relaxation of the bronchi, and an increased rate and contractility of the heart. Each of these receptors is subdivided further into two types. Alpha1 receptors are postsynaptic; alpha2 receptors are situated on the presynaptic membrane and, when stimulated, diminish the release of the transmitter. Beta1 receptors are, for all practical purposes, limited to the heart; their activation increases the heart rate and contractility. Beta2 receptors, when stimulated, relax the smooth muscle of the bronchi and of most other sites, including the blood vessels of skeletal muscle. A comprehensive account of neurohumoral transmission and receptor function can be found in the monograph by Cooper and colleagues.


Neurology_Adams

Neurology_Adams. Discussed in the following pages are the ways in which the two divisions of the autonomic nervous system, acting in conjunction with the endocrine glands, maintain the homeostasis of the organism. As stated earlier, the integration of these two systems is achieved primarily in the hypothalamus. In addition, the endocrine glands are influenced by circulating catecholamines, and some of them are innervated by adrenergic fibers. Chapter 26 discusses further these autonomic–endocrine relations. Regulation of Blood Pressure


Neurology_Adams

Neurology_Adams. As was indicated briefly in Chap. 17, blood pressure depends on the adequacy of intravascular blood volume, on systemic vascular resistance, and on the cardiac output. Both the autonomic and endocrine systems influence the muscular, cutaneous, and mesenteric (splanchnic) vascular beds, heart rate, and stroke volume of the heart. Together, these actions serve to maintain normal blood pressure and allow reflex maintenance of blood pressure with changes in body position. Two types of baroreceptors function as the afferent component of this reflex arc by sensing pressure gradients across the walls of large blood vessels. Those in the carotid sinus and aortic arch are sensitive to reductions in pulse pressure (the difference between systolic and diastolic blood pressure), while those in the right heart chambers and pulmonary vessels respond more to alterations in blood volume. The carotid sinus baroreceptors are rapidly responsive and capable of detecting beat-to-beat changes, in contrast


Neurology_Adams

Neurology_Adams. heart chambers and pulmonary vessels respond more to alterations in blood volume. The carotid sinus baroreceptors are rapidly responsive and capable of detecting beat-to-beat changes, in contrast to the aortic arch nerves, which have a longer response time and discriminate only the larger and more prolonged alterations in pressure.


Neurology_Adams

Neurology_Adams. The nerves arising from these receptors are small-caliber, thinly myelinated fibers that course in cranial nerves IX and X and terminate in the nucleus of the tractus solitarius (NTS). In response to increased stimulation of these receptors, vagal efferent activity is reduced, resulting in reflex cardioacceleration. This is accomplished through polysynaptic connections between the NTS and the dorsal motor nucleus of the vagus; it is from this structure that vagal neurons project to the sinoatrial node, atrioventricular node, and the muscle of the left ventricle. Thus, vagal activity results in reduction in heart rate and in the contractile force of the myocardium (negative inotropy). Increased systemic vascular resistance is mediated concurrently through parallel connections between the NTS and the medullary pressor areas that project to the intermediolateral cells of the midthoracic cord. The main sympathetic outflow from these thoracic segments is via the greater splanchnic nerve to


Neurology_Adams

Neurology_Adams. and the medullary pressor areas that project to the intermediolateral cells of the midthoracic cord. The main sympathetic outflow from these thoracic segments is via the greater splanchnic nerve to the celiac ganglion, the postganglionic nerves of which project to the capacitance vessels of the gut. The splanchnic capacitance veins act as a reservoir for as much as 20 percent of the total blood volume, and interruption of the splanchnic nerves results in severe postural hypotension. After a high-carbohydrate meal there is a marked hyperemia of the gut and compensatory peripheral vasoconstriction in the muscles and skin. It has also been noted that the mesenteric vascular bed is responsive to the orthostatic redistribution of blood volume but not to mental stress.


Neurology_Adams

Neurology_Adams. The opposite response to the one described earlier, namely bradycardia and hypotension, results when vagal tone is enhanced and sympathetic tone reduced. This response can be triggered by baroreceptors, or it may arise from cerebral stimuli such as fear or sight of blood in susceptible individuals as well as from extreme pain, particularly arising in the viscera.


Neurology_Adams

Neurology_Adams. Two slower-acting humoral mechanisms regulate blood volume and complement the control of systemic vascular resistance. Pressure-sensitive renal juxtaglomerular cells release renin, which stimulates production of angiotensin and influences aldosterone production, both of which affect an increase of blood volume. Of lesser influence in the control of blood pressure is antidiuretic hormone, discussed in the next chapter; but the effects of this peptide become more important when autonomic failure forces a dependence on secondary mechanisms for the maintenance of blood pressure. In addition to its presence in autonomic ganglia, nitric oxide has been found to have an important local role in maintaining vascular tone, mainly by way of attenuating the response to sympathetic stimulation. The extent to which this latter function is under neural control is not clear. Regulation of Bladder Function


Neurology_Adams

Neurology_Adams. The familiar functions of the bladder and lower urinary tract—the storage and intermittent evacuation of urine—are served by three structural components: the bladder itself, the main component of which is the large detrusor (transitional type) muscle; a functional internal sphincter composed of similar muscle; and the striated external sphincter or urogenital diaphragm. The sphincters ensure continence; in the male, the internal sphincter also prevents the reflux of semen from the urethra during ejaculation. For micturition to occur, the sphincters must relax, allowing the detrusor to expel urine from the bladder into the urethra. This is accomplished by a complex mechanism involving mainly the parasympathetic nervous system (the sacral peripheral nerves derived from the second, third, and fourth sacral segments of the spinal cord and their somatic sensorimotor fibers) and, to a lesser extent, sympathetic fibers derived from the thorax. The vaguely localizable brainstem “micturition


Neurology_Adams

Neurology_Adams. fourth sacral segments of the spinal cord and their somatic sensorimotor fibers) and, to a lesser extent, sympathetic fibers derived from the thorax. The vaguely localizable brainstem “micturition centers,” with their spinal and suprasegmental connections, may contribute (Fig. 25-4).


Neurology_Adams

Neurology_Adams. The detrusor muscle receives motor innervation from nerve cells in the intermediolateral columns of gray matter, mainly from the third and also from the second and fourth sacral segments of the spinal cord (the “detrusor center”). These neurons give rise to preganglionic fibers that synapse in parasympathetic ganglia within the bladder wall. Short postganglionic fibers end on muscarinic acetylcholine receptors of the muscle fibers. There are also beta-adrenergic receptors in the dome of the bladder, which are activated by sympathetic fibers that arise in the intermediolateral nerve cells of T10, T11, and T12 segments. These preganglionic fibers pass via inferior splanchnic nerves to the inferior mesenteric ganglia (see Fig. 25-1); preand postganglionic sympathetic axons are conveyed by the hypogastric nerve to the pelvic plexus and the bladder dome. The internal sphincter and base of the bladder (trigone), consisting of smooth muscle, are also innervated to some extent by the


Neurology_Adams

Neurology_Adams. by the hypogastric nerve to the pelvic plexus and the bladder dome. The internal sphincter and base of the bladder (trigone), consisting of smooth muscle, are also innervated to some extent by the sympathetic fibers of the hypogastric nerves; their receptors are mainly of alpha-adrenergic type, which makes it possible to therapeutically manipulate the function of the sphincter with adrenergically active drugs as well as the more commonly used cholinergic ones (see further on).


Neurology_Adams

Neurology_Adams. The external urethral and anal sphincters are composed of striated muscle fibers. Their innervation, via the pudendal nerves, is derived from a densely packed group of somatomotor neurons (nucleus of Onuf) in the anterolateral horns of sacral segments 2, 3, and 4. Cells in the ventrolateral part of Onuf’s nucleus innervate the external urethral sphincter, and cells of the mediodorsal part innervate the anal sphincter. The muscle fibers of the sphincters respond to the nicotinic effects of ACh.


Neurology_Adams

Neurology_Adams. The pudendal nerves also contain afferent fibers coursing from the urethra and the external sphincter to the sacral segments of the spinal cord. These fibers convey impulses for reflex activities and, through connections with higher centers, for sensation. Some of these fibers probably course through the hypogastric plexus, as indicated by the fact that patients with complete transverse lesions of the cord as high as T12 may report vague sensations of urethral discomfort. The bladder is sensitive to pain and pressure; these senses are transmitted to higher centers along the sensory pathways described in Chaps. 7 and 8.


Neurology_Adams

Neurology_Adams. Unlike skeletal striated muscle, the detrusor, because of its postganglionic system, is capable of some contractions, although imperfect, after complete destruction of the sacral segments of the spinal cord. Isolation of the sacral cord centers (transverse lesions of the cord above the sacral levels) and their peripheral nerves permits contractions of the detrusor muscle, but they still do not empty the bladder completely; patients with such lesions usually develop dyssynergia of the detrusor and external sphincter muscles (see later), indicating that coordination of these muscles must occur at supraspinal levels (Blaivas). With acute transverse lesions of the upper cord, the function of sacral segments is abolished for several weeks in the same way as the motor neurons of skeletal muscles (the state of spinal shock).


Neurology_Adams

Neurology_Adams. The storage of urine and the efficient emptying of the bladder are possible only when the spinal segments, together with their afferent and efferent nerve fibers, are connected with the so-called micturition centers in the pontomesencephalic tegmentum. In experimental animals, this center (or centers) lies within or adjacent to the locus ceruleus. A medial region triggers micturition, while a lateral area seems more important for continence. These neurons receive afferent impulses from the sacral cord segments; their efferent fibers course downward via the reticulospinal tracts in the lateral funiculi of the spinal cord and activate cells in the nucleus of Onuf, as well as in the intermediolateral cell groups of the sacral segments (Holstege and Tan). In cats, the pontomesencephalic centers receive descending fibers from anteromedial parts of the frontal cortex, thalamus, hypothalamus, and cerebellum, but the brainstem centers and their descending pathways have not been precisely


Neurology_Adams

Neurology_Adams. receive descending fibers from anteromedial parts of the frontal cortex, thalamus, hypothalamus, and cerebellum, but the brainstem centers and their descending pathways have not been precisely defined in humans. Other fibers from the motor cortex descend with the corticospinal fibers to the anterior horn cells of the sacral cord and innervate the external sphincter. According to Ruch, the descending pathways from the midbrain tegmentum are inhibitory and those from the pontine tegmentum and posterior hypothalamus are facilitatory. The pathway that descends with the corticospinal tract from the motor cortex is inhibitory. Thus the net effect of lesions in the brain and spinal cord on the micturition reflex, at least in animals, may be either inhibitory or facilitatory (DeGroat).


Neurology_Adams

Neurology_Adams. Almost all of this information has been inferred from animal experiments; there is little human pathologic material to corroborate the role of brainstem nuclei and cortex in bladder control. What information is available is reviewed extensively by Fowler, whose article is recommended. Also of interest here is the study by Blok and colleagues, who performed positron emission tomography (PET) studies in volunteer subjects during micturition. Increased blood flow was detected in the right pontine tegmentum, periaqueductal region, hypothalamus, and right inferior frontal cortex. When the bladder was full but subjects were prevented from voiding, increased activity was seen in the right ventral pontine tegmentum. The meaning of these lateralized findings is unclear, but the study supports the presumption that pontine centers are involved in the act of voiding.


Neurology_Adams

Neurology_Adams. The act of micturition is both reflex and voluntary. When the normal person desires to void, there is first a voluntary relaxation of the perineum, followed sequentially by an increased tension of the abdominal wall, a slow contraction of the detrusor, and an associated opening of the internal sphincter; finally, there is a relaxation of the external sphincter (Denny-Brown and Robertson). It is useful to think of the detrusor contraction as a spinal stretch reflex, subject to facilitation and inhibition from higher centers. Voluntary closure of the external sphincter and contraction of the perineal muscles cause the detrusor contraction to subside. The abdominal muscles have little role in initiating micturition except when the detrusor muscle is not functioning normally. The voluntary restraint of micturition is a cerebral affair and is mediated by fibers that arise in the frontal lobes (paracentral motor region), descend in the spinal cord just anterior and medial to the


Neurology_Adams

Neurology_Adams. restraint of micturition is a cerebral affair and is mediated by fibers that arise in the frontal lobes (paracentral motor region), descend in the spinal cord just anterior and medial to the corticospinal tracts, and terminate on the cells of the anterior horns and intermediolateral cell columns of the sacral segments, as described earlier. The coordination of detrusor and external sphincteric function depends mainly on the descending pathway from the posited centers in the dorsolateral pontine tegmentum.


Neurology_Adams

Neurology_Adams. Regulation of Bowel Function The colon and anal sphincters are obedient to the same principles that govern bladder function. Unique to the bowel, however, is an intrinsic enteric nervous system that originates in the myenteric (or Auerbach) plexus and the submucosal plexus (of Meissner), located in the gut wall. The first stimulates smooth muscle and the latter also regulates mucosal secretion and blood flow. This embedded system controls peristalsis largely independent of other autonomic influences but is highly responsive to local chemical and mechanical stimuli. As outlined in the thorough review by Benarroch that should be consulted by interested readers, acetylcholine is the dominant neurotransmitter in the enteric nerves but nitric oxide and numerous peptide transmitters are found in profusion.


Neurology_Adams

Neurology_Adams. The autonomic nervous system and the adrenal glands were accepted for many years as the neural and humoral basis of all instinctive and emotional behavior. In states of chronic anxiety and acute panic reactions, depressive psychosis, mania, and schizophrenia, all of which are characterized by an altered emotionality, no consistent autonomic or endocrine dysfunction has been demonstrated except perhaps for diminished responses of growth hormone in panic disorders. The lack of cortisol suppressibilty by injection of adrenocorticotropic hormone (ACTH) had for some time also been considered to be a consistent aspect of depressive illnesses but that too, has not been entirely specific. This has been disappointing, as the emergency theory of sympathoadrenal action provided by Cannon was such a promising concept of the neurophysiology of acute emotion, and Selye had extended this theory so plausibly to explain all the reactions to stress in animals and humans.


Neurology_Adams

Neurology_Adams. According to these theories, strong emotion, such as anger or fear, excites the sympathetic nervous system and the adrenal cortex (via corticotropin-releasing factor [CRF] and ACTH), which are under direct neural and endocrine control. These sympathoadrenal reactions are brief and sustain the animal in “flight or fight” as discussed in Chap. 24. Animals deprived of adrenal cortex or human beings with Addison disease cannot tolerate stress because they are incapable of mobilizing both the adrenal medulla and adrenal cortex. Prolonged stress and production of ACTH activates all the adrenal hormones (glucocorticoids, mineralocorticoids, and adrenocorticoids) and has been studied extensively in relation to immune reactions and other systemic functions but with no consistent findings that are yet clinically applicable. Tests for Abnormalities of the Autonomic Nervous System


Neurology_Adams

Neurology_Adams. Tests for Abnormalities of the Autonomic Nervous System With few exceptions, such as testing pupillary reactions and examination of the skin for abnormalities of color and sweating, the neurologist tends to be casual in evaluating the function of the autonomic nervous system. Nonetheless, several simple but informative tests can be used to confirm one’s clinical impressions and to elicit abnormalities of autonomic function that may aid in diagnosis. For the detection of certain disease, it is almost imperative that blood pressure be evaluated to detect a drop with change in body position from lying or sitting, to standing. A combination of tests is usually necessary, because certain ones are particularly sensitive to abnormalities of sympathetic function and others to parasympathetic or baroreceptor afferent function. These are described later and are summarized in Table 25-1. A scheme for the examination of pupillary abnormalities was presented in Fig. 13-11.


Neurology_Adams

Neurology_Adams. Testing of Blood Pressure and Heart Rate


Neurology_Adams

Neurology_Adams. These are among the simplest and most important tests of autonomic function and most laboratories have automated techniques to quantitate them. McLeod and Tuck state that in changing from the recumbent to the standing position, a fall of more than 30 mm Hg systolic and 15 mm Hg diastolic is abnormal; others give figures of 20 and 10 mm Hg. They caution that the arm on which the cuff is placed must be held horizontally when standing, so that the decline in arm pressure will not be obscured by the added hydrostatic pressure. As emphasized in Chap. 17 on syncope, the determination of blood pressure in orthostatic testing is ideally done by having the patient remain supine for as long as it is practical before testing, and shifting from a supine to standing position, without the interposition of sitting. Moreover, blood pressure is most informative if measured immediately after standing and again at approximately 1 and 3 min. The expected response is a momentary and slight increase in


Neurology_Adams

Neurology_Adams. of sitting. Moreover, blood pressure is most informative if measured immediately after standing and again at approximately 1 and 3 min. The expected response is a momentary and slight increase in pressure that is usually not detected with a manual blood pressure cuff, followed by a slight drop within seconds of standing, and then a slow recovery during the first minute. Persistent hypotension at 1 min indicates sympathetic adrenergic failure and the later measurement affirms this if blood pressure fails to recover or continues to decline (Fig. 25-5).


Neurology_Adams

Neurology_Adams. The main cause of an orthostatic drop in blood pressure is, of course, hypovolemia. In the context of recurrent fainting, however, an excessive drop reflects inadequate sympathetic vasoconstrictor activity. The use of a tilt table, as described in “Tilt-Table Testing” in Chap. 17 and further on, is an additional means of inducing orthostatic changes and also elicits reflex fainting in patients prone to syncope from an oversensitive cardiac reflex, that is, one that produces vasodilatation (neurocardiogenic syncope). In response to the induced drop in blood pressure, the heart rate (mainly under vagal control) normally increases. The failure of the heart rate to rise in response to the drop in blood pressure with standing is the simplest bedside indicator of vagal nerve dysfunction. Neurally mediated syncope may show one of three initial patterns with testing on a tilt table: a vasodepressor response alone (vasodepressor syncope), a combined bradycardic and hypotensive response (mixed


Neurology_Adams

Neurology_Adams. mediated syncope may show one of three initial patterns with testing on a tilt table: a vasodepressor response alone (vasodepressor syncope), a combined bradycardic and hypotensive response (mixed syncope), and solely bradycardia (cardiovagal syncope) (Fig. 25-6). The mixed syncope is the most common form of neurally mediated syncope. The tilt table allows differentiation among these or, more often, clarifies the order in which the events occur.


Neurology_Adams

Neurology_Adams. In addition, the heart rate, after rising initially in response to upright standing posture (not with the tilt table), slows after about 15 beats to reach a stable rate by the thirtieth beat. The ratio of R-R intervals in the electrocardiogram (ECG), corresponding to the 30th and 15th beats (the 30:15 ratio), is an even more sensitive measure of the integrity of vagal inhibition of the sinus node. A ratio in adults under age 60 of less than 1.07 is usually abnormal, indicating a loss of vagal tone and the normal ratio is progressively higher for younger ages, for example, it is usually above 1.12 at age 30 and 1.1 at age 40.


Neurology_Adams

Neurology_Adams. Another simple procedure for quantitating purely vagal function consists of measuring the variation in heart rate during deep breathing (respiratory sinus arrhythmia). The ECG is recorded while the patient breathes at a regular rate of 6 breaths per minute. Normally, the heart rate varies by as many as 10 beats per minute or even more between expiration and inspiration; differences of less than 7 beats per minute for ages 60 to 69 and 9 for ages 50 to 59 may be abnormal.


Neurology_Adams

Neurology_Adams. A yet more accurate test of vagal function is the measurement of the ratio of the longest R-R interval during forceful slow expiration (standardized as constant blowing at a pressure of 40 mm Hg for 10 s) to the shortest R-R interval during inspiration, which allows the derivation of an expiration–inspiration (E:I) ratio. This is the best validated of all the heart-rate measurements, particularly as computerized methods can be used to display the spectrum of beat-to-beat ECG intervals during breathing. The results of these tests must always be compared with those obtained in normal individuals of the same age. Up to age 40 years, E:I ratios of less than 1.2 (signifying a variation of 20 percent) are abnormal. The ratio decreases with age, and markedly so beyond age 60 years (at which time it approaches 1.04 or less), as it does also in the presence of even mild diabetic neuropathy. Thus the test results must be interpreted cautiously in the elderly or in diabetic individuals. Similar


Neurology_Adams

Neurology_Adams. it approaches 1.04 or less), as it does also in the presence of even mild diabetic neuropathy. Thus the test results must be interpreted cautiously in the elderly or in diabetic individuals. Similar ratios have been developed for heart-rate change during the Valsalva maneuver; the Valsalva ratio.


Neurology_Adams

Neurology_Adams. Computerized methods of power spectral analysis may be used to express the variance in heart rate as a function of the beat-to-beat interval. Several power peaks are appreciated: one related to the respiratory sinus arrhythmia and others that reflect baroreceptor and cardiac sympathetic activity. All of these tests of heart-rate variation are usually combined with measurement of heart rate and blood pressure during the Valsalva maneuver, as described below, and with the tilt-table test, as described in Chap. 17.


Neurology_Adams

Neurology_Adams. In the Valsalva maneuver, the subject exhales into a manometer or against a closed glottis for 10 s, creating a markedly positive intrathoracic pressure. The sharp reduction in venous return to the heart causes a drop in cardiac output and in blood pressure; the response on baroreceptors is to cause a reflex tachycardia and, to a lesser extent, peripheral vasoconstriction. With release of intrathoracic pressure, the venous return, stroke volume, and blood pressure rise to higher-than-normal levels; reflex parasympathetic influence then predominates and a bradycardia results (see Fig. 25-5). Failure of the heart rate to increase during the positive intrathoracic pressure phase of the Valsalva maneuver points to sympathetic dysfunction, and failure of the rate to slow during the period of blood pressure overshoot points to a parasympathetic disturbance. In patients with autonomic failure, the fall in blood pressure is not aborted during the last few seconds of increased intrathoracic


Neurology_Adams

Neurology_Adams. blood pressure overshoot points to a parasympathetic disturbance. In patients with autonomic failure, the fall in blood pressure is not aborted during the last few seconds of increased intrathoracic pressure, and there is no overshoot of blood pressure when the breath is released. The Valsalva ratio, referring to the maximum heart rate generated by the maneuver to the lowest heart rate within 30 s of that peak, is another often-used measure in comprehensive autonomic testing.


Neurology_Adams

Neurology_Adams. Tests of Vasomotor Reactions These generally test sympathetic cholinergic function. Measurement of the skin temperature is a rough but useful index of vasomotor function. Vasomotor paralysis results in vasodilatation of skin vessels and a rise in skin temperature; vasoconstriction lowers the temperature. With a skin thermometer, one may compare affected and normal areas under standard conditions. The normal skin temperature is 31°C (87.8°F) to 33°C (91.4°F) when the room temperature is 26°C (78.8°F) to 27°C (80.6°F). Vasoconstrictor tone may also be tested by measuring the reduction in skin temperature at a distant site before and after immersing one or both hands in cold water (see the discussion of the cold pressor test later).


Neurology_Adams

Neurology_Adams. The integrity of the sympathetic reflex arc, which includes baroreceptors in the aorta and carotid sinus, their afferent pathways, the vasomotor centers, and the sympathetic and parasympathetic outflow can be tested in a general way by combining the cold pressor test, grip test, mental arithmetic test, and Valsalva maneuver, as described below.


Neurology_Adams

Neurology_Adams. Vasoconstriction induces an elevation of the blood pressure. This is the basis of the cold pressor test. In normal persons, immersing one hand in ice water for 1 to 5 min raises the systolic pressure by 15 to 20 mm Hg and the diastolic pressure by 10 to 15 mm Hg. Similarly, the sustained isometric contraction of a group of muscles (e.g., those of the forearm in handgrip) for 5 min normally increases the heart rate and the systolic and diastolic pressures by at least 15 mm Hg. The response in both of these tests is reduced or absent with lesions of the sympathetic reflex arc, particularly of the efferent limb, but neither of these tests has been well quantitated or validated. The stress involved in doing mental arithmetic in noisy and distracting surroundings will also stimulate a mild but measurable increase in pulse rate and blood pressure. Obviously this response does not depend on the afferent limb of the sympathetic reflex arc and must be mediated by cortical–hypothalamic


Neurology_Adams

Neurology_Adams. mild but measurable increase in pulse rate and blood pressure. Obviously this response does not depend on the afferent limb of the sympathetic reflex arc and must be mediated by cortical–hypothalamic mechanisms.


Neurology_Adams

Neurology_Adams. If the response to the Valsalva maneuver is abnormal and the response to the cold pressor test is normal, the lesion is probably in the baroreceptors or their afferent nerves; such a defect has been found in diabetic and tabetic patients and is common in many neuropathies. A failure of the heart rate and blood pressure to rise during mental arithmetic coupled with an abnormal Valsalva maneuver suggests a defect in the central or peripheral efferent sympathetic pathways. Tests of Sudomotor Function


Neurology_Adams

Neurology_Adams. Tests of Sudomotor Function The integrity of sympathetic efferent pathways can be assessed further by tests of sudomotor activity. There are several of these, all used mainly in specialized autonomic testing laboratories. The most rudimentary tests involve weighing sweat after it is absorbed by small squares of filter paper. Also, powdered charcoal dusted on the skin will cling to moist areas and not to dry ones. The starch iodine (Minor) is a qualitative test, which uses color changes of cornstarch dusted on the skin covered with tincture iodine. Minor’s tests can be used to detect hypoor hyperhidrosis. Previously described quinizarin (gray when dry, purple when wet) uses similar principle. The methods described above reflect postganglionic sudomotor function.


Neurology_Adams

Neurology_Adams. In the sympathetic or galvanic skin-resistance test, a set of electrodes placed on the skin measures the resistance to the passage of a weak current through the skin; in all likelihood, the change in electrical potential is the result of an ionic current within the sweat glands, not simply an increase in sweating that lowers skin resistance. This method can be used to outline an area of reduced sweating because of a peripheral nerve lesion, as the response depends on sympathetic activation of sweat glands (Gutrecht). However, the galvanic skin response is subject to habituation with repeated stimuli and will show no response if there is a sensory neuropathy. The silicone imprint method is a quantitative postganglionic test that measures sweat droplets induced by iontophoresis of acetylcholine, pilocarpine, or methacholine. Although in theory quantitative, the imprint methods are prone to artefacts (see Stewart et al).


Neurology_Adams

Neurology_Adams. A more quantitative and reproducible examination of postganglionic sudomotor function, termed QSART (quantitative sudomotor axon reflex test), has been developed and studied extensively by Low. It is essentially a test of distal sympathetic axonal integrity utilizing the local axon reflex. A 10 percent solution of acetylcholine is iontophoresed onto the skin using 2 mA for 5 min. Sweat output is recorded in the adjacent skin by sophisticated circular cells that detect the sweat water. The forearm, proximal leg, distal leg, and foot have been chosen as standardized recording sites. By this test, Low has been able to define patterns of absent or delayed sweating that signify postganglionic sympathetic failure in small-fiber neuropathies and excessive sweating or reduced latency in response, as is seen in reflex sympathetic dystrophy. This is the preferred method of studying sweating and the function of distal sympathetic fibers, but its technical complexity makes it available only in


Neurology_Adams

Neurology_Adams. as is seen in reflex sympathetic dystrophy. This is the preferred method of studying sweating and the function of distal sympathetic fibers, but its technical complexity makes it available only in specially equipped laboratories.


Neurology_Adams

Neurology_Adams. The thermoregulatory sweat testing (TST) measures the integrity of the central and peripheral sympathetic sudomotor pathways. The test is conducted by raising the core body temperature by increasing the ambient temperature and the sweating pattern is visualized with an indicator dye. This may show striking results but is time consuming, needs special patient preparation, and large clinical space. The advantage of TST is that in combination with tests measuring postganglionic functions, it can differentiate between postganglionic (all tests abnormal) versus preganglionic (only TST abnormal) failure.


Neurology_Adams

Neurology_Adams. Tearing can be estimated roughly by inserting one end of a 5-mm-wide and 25-mm-long strip of thin filter paper into the lower conjunctival sac while the other end hangs over the edge of the lower lid (the Schirmer test). The tears wet the strip of filter paper, producing a moisture front. After 5 min, the moistened area extends for a length of approximately 15 mm in normal persons. An extent of less than 10 mm is suggestive of hypolacrima. This test is used mainly to detect the dry eyes (keratoconjunctivitis sicca) of the Sjögren syndrome, but it may also be helpful in fully studying various autonomic neuropathies. Tests of Bladder, Gastrointestinal, and Penile Erectile Function


Neurology_Adams

Neurology_Adams. Tests of Bladder, Gastrointestinal, and Penile Erectile Function Bladder function is best assessed by the cystometrogram, which measures intravesicular pressure as a function of the volume of saline solution permitted to flow by gravity into the bladder. The rise of pressure as 500 mL of fluid is allowed to flow gradually into the bladder, the emptying contractions of the detrusor, and the volume at which the patient reports a sensation of bladder fullness can be recorded by a manometer. (A detailed account of cystometric techniques can be found in the monograph of Krane and Siroky.) A simple way of determining bladder atony (prostatic obstruction and overdistention having been excluded) is to measure the residual urine (by catheterization of the bladder) immediately after voluntary voiding or to estimate its volume by ultrasound imaging.


Neurology_Adams

Neurology_Adams. Disorders of gastrointestinal motility are readily demonstrated radiologically. In dysautonomic states, a barium swallow may disclose a number of abnormalities, including atonic dilatation of the esophagus, gastric atony and distention, delayed gastric emptying time, and a characteristic small bowel pattern consisting of an increase in frequency and amplitude of peristaltic waves and rapid intestinal transit. A barium enema may demonstrate colonic distention and a decrease in propulsive activity. Sophisticated manometric techniques are now available for the measurement of gastrointestinal motility (see Low et al). Nocturnal penile tumescence is recorded in some sleep laboratories and may be used as an ancillary test of sacral autonomic (parasympathetic) innervation. Pharmacologic Tests of Autonomic Function


Neurology_Adams

Neurology_Adams. Nocturnal penile tumescence is recorded in some sleep laboratories and may be used as an ancillary test of sacral autonomic (parasympathetic) innervation. Pharmacologic Tests of Autonomic Function After examining the pupils in ambient light, bright light, and low light to determine if one has lost sympathetic or parasympathetic innervation, pharmacologic tests can be used to refine diagnosis. Part of the rationale behind these special tests is the “Cannon law,” or the phenomenon of denervation hypersensitivity, in which an effector organ, 2 to 3 wk after denervation, becomes hypersensitive to its particular neurotransmitter substance and related drugs. In clinical testing, an agent is instilled into both conjunctival sacs and the nonmiotic pupil is used as a control to compare the one suspect of being involved by Horner syndrome.


Neurology_Adams

Neurology_Adams. Relatively recently, the weak direct sympathetic agonist apraclonidine has been used most widely to demonstrate that miosis is due to sympathetic denervation of the pupil. It reverses miosis that is due to a central or a peripheral lesion and is easier to obtain then older agents. A positive test, reversal of miosis, depends on the denervation hypersensitivity that develops after several days or more of the presence of the Horner syndrome. If there is a negative result, no enlargement of the pupil, the miosis is probably physiologic. The drug has the additional advantage of often reversing the ptosis of Horner syndrome (see Chap. 13 and Fig. 13-10 for discussion). The drug may cause respiratory suppression in children and is avoided.


Neurology_Adams

Neurology_Adams. Once the presence of a genuine Horner syndrome has been established, it is possible to differentiate prefrom postganglionic (superior cervical ganglion) sympathetic denervation of the pupil by instilling 1 percent hydroxyamphetamine; its effect depends on the presence of existing norepinephrine in the end terminals of the nerves that innervate the iris. Failure to dilate indicates a postganglionic lesion.


Neurology_Adams

Neurology_Adams. Another test, now used mostly in children, in whom apraclonidine represents a risk, is the topical application into the conjunctival sac of a 4 to 10 percent cocaine solution that potentiates the effects of NE by preventing its reuptake. A normal response to cocaine consists of pupillary dilatation. In sympathetic denervation caused by lesions of the postor preganglionic fibers, no change in pupillary size occurs because no transmitter substance is available and the cocaine has no substrate to potentiate. The reason for lack of response in chronic preganglionic lesions is presumed to be a depletion of NE in the postganglionic fibers. In cases of central sympathetic lesions, slight mydriasis may occur.


Neurology_Adams

Neurology_Adams. The intracutaneous injection of 0.05 mL of 1:1,000 histamine normally causes a 1-cm wheal after 5 to 10 min. This is surrounded by a narrow red areola, which in turn, is surrounded by an erythematous flare that extends 1 to 3 cm beyond the border of the wheal. A similar “triple response” follows the release of histamine into the skin as the result of a scratch. It can be elicited in sensitive individuals by scratching the skin (dermatographia).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. At the bedside, the most convenient ones are measurement of orthostatic heart rate and blood pressure changes, blood pressure response to the Valsalva maneuver, estimation of heart-rate changes with deep breathing, pupillary responses to light and dark, and a rough estimate of sweating of the palms and soles and with lesions of the spinal cord, on the trunk. The results of these tests and the clinical situation will determine whether further testing is needed.


Neurology_Adams

Neurology_Adams. Since this condition was first reported by Young and colleagues in 1975, many more cases in both adults and children have been placed on record. Over a period of a week or a few weeks with or without a preceding systemic or respiratory infection, the patient develops some combination of anhidrosis, orthostatic hypotension, paralysis of pupillary reflexes, loss of lacrimation and salivation, erectile dysfunction, impaired bladder and bowel function (urinary retention, postprandial bloating, and ileus or constipation), and loss of certain pilomotor and vasomotor responses in the skin (flushing and heat intolerance). Fatigue, sometimes severe, is a prominent complaint in most patients, and abdominal pain and vomiting in others. A few develop sleep apnea or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), leading to hyponatremia. The cerebrospinal fluid (CSF) protein is normal or slightly increased.


Neurology_Adams

Neurology_Adams. Clinical and laboratory findings indicate that both the sympathetic and parasympathetic parts of the autonomic nervous system are affected, mainly at the postganglionic level. Somatosensory and motor nerve fibers appear to be spared or are affected to only a slight extent, although many patients complain of paresthesias, and tendon reflexes are frequently lost. In one of the patients described by Low and colleagues, there was physiologic and morphologic (sural biopsy) evidence of loss of small myelinated and unmyelinated somatic fibers and foci of epineurial mononuclear cells; in other cases, sural nerve fiber counts have been normal; and in an autopsied case, in which there had also been sensory loss, there was lymphocytic infiltration in sensory and autonomic nerves (Fagius et al). The original patient described by Young and colleagues and most of the other patients reported with pure dysautonomia are said to have recovered completely or almost so within several months, but many of


Neurology_Adams

Neurology_Adams. original patient described by Young and colleagues and most of the other patients reported with pure dysautonomia are said to have recovered completely or almost so within several months, but many of our patients have been left with disordered gastrointestinal and sexual functions. In addition to an idiopathic form of autonomic paralysis, some cases are postinfectious, and there is a similar but rare paraneoplastic form (see Chap. 30 under “Paraneoplastic Sensory Neuronopathy”). Antibodies against ganglionic acetylcholine receptors have been found in half of idiopathic cases and one-quarter of paraneoplastic ones (Vernino et al).


Neurology_Adams

Neurology_Adams. Some children with this disease and a few adults have had a syndrome of predominantly cholinergic dysautonomia with pain and dysesthesias (Kirby et al); there is little or no postural hypotension and the course has been more chronic than that in cases of complete dysautonomia described earlier.


Neurology_Adams

Neurology_Adams. In view of the identical autonomic disturbances in the Guillain-Barré syndrome and the high incidence of minor degrees of weakness, reflex loss, CSF protein elevation, and especially paresthesias, it is likely that pure pandysautonomia is also an immune-mediated polyneuropathy affecting the autonomic fibers within peripheral nerves, in most ways comparable to the Guillain-Barré syndrome. The aforementioned autopsy findings reported by Fagius and coworkers support such a relationship. In animals, autonomic paralysis has been produced by injection of extracts of sympathetic ganglia and Freund’s adjuvant (Appenzeller et al), similar to the experimental immune neuritis that is considered as an animal model of the Guillain-Barré syndrome.


Neurology_Adams

Neurology_Adams. An acquired form of orthostatic intolerance, referred to as sympathotonic orthostatic hypotension (Polinsky et al), may represent another variant or partial form of autonomic paralysis. In this syndrome, unlike the common forms of orthostatic hypotension (see later), the fall in blood pressure is accompanied by tachycardia. Hoeldtke and colleagues, who described 4 such patients, found that the vasomotor reflexes and NE production were normal; these investigators were inclined to attribute the disorder to a process affecting lower thoracic and lumbar sympathetic neurons. Its relationship to the entity of postural orthostatic tachycardia syndrome (POTS) discussed in Chap. 17 and to the orthostatic intolerance associated with the chronic fatigue syndrome is uncertain. Individual cases of POTS have been associated with mutations or epigenetic alterations in the norepinephrine transporter gene (Shannon and colleagues, 2005). Some instances of orthostatic intolerance appear as part of the


Neurology_Adams

Neurology_Adams. have been associated with mutations or epigenetic alterations in the norepinephrine transporter gene (Shannon and colleagues, 2005). Some instances of orthostatic intolerance appear as part of the asthenia–anxiety disorders in which the autonomic changes may represent sympathetic overactivity in susceptible individuals.


Neurology_Adams

Neurology_Adams. There are several reports of improvement of pandysautonomia after intravenous gamma globulin infusion, but these are difficult to judge as many patients improve spontaneously over the same time frame, usually many months. In addition, plasma exchange has been used with apparent benefit in a patient with antibodies against the ganglionic acetylcholine receptor (Schroeder et al).


Neurology_Adams

Neurology_Adams. As more experience accumulated over years, it became apparent that acute autonomic neuropathies represent a spectrum of disorders and majority are likely immune-mediated. These disorders include acute autoimmune ganglionopathy—idiopathic or paraneoplastic, (previously called panautonomic neuropathy or pandysautonomia) characterized by severe and widespread sympathetic and parasympathetic failure. Other forms of acute autonomic neuropathies are acute cholinergic neuropathy, Guillain-Barré syndrome, botulism, porphyria, drug-induced or toxic. Restricted forms of acute autonomic neuropathies may results in postural tachycardia syndrome or motility disorders. Some patients with acute autonomic neuropathies have autoantibodies to the A3 acetylcholine receptor. Somatic involvement of variable severity is seen in majority of acute autonomic neuropathies.


Neurology_Adams

Neurology_Adams. Lambert-Eaton myasthenic syndrome One of the characteristic features of the fully developed Lambert-Eaton myasthenic syndrome, which is discussed in Chap. 46, is dysautonomia, characterized by dryness of the mouth, erectile dysfunction, difficulty in starting the urinary stream, and constipation. Presumably, circulating antibodies against the voltage-gated calcium channel interfere with the release of ACh at both muscarinic and nicotinic sites. Multiple System Atrophy and Pure Autonomic Failure (See Also Chaps. 17 and 38)


Neurology_Adams

Neurology_Adams. The clinical state of idiopathic orthostatic hypotension is now known to be caused by at least two conditions. One is a degenerative disease of middle and late adult life, first described by Bradbury and Eggleston in 1925 and designated by them as idiopathic orthostatic hypotension and by subsequent authors, “primary autonomic failure.” In this disorder, the lesions involve mainly the postganglionic sympathetic neurons (Petito and Black); the parasympathetic system is relatively spared and the CNS is uninvolved. In the second more common disorder that is now classified as a multiple system atrophy, described initially by Shy and Drager, the preganglionic lateral horn neurons of the thoracic spinal segments degenerate; these changes are responsible for the orthostatic hypotension. Later, signs of basal ganglionic or cerebellar disease or both are added as discussed later and in Chaps. 17 and 38 but a few cases remain as a pure autonomic failure. In both types of orthostatic


Neurology_Adams

Neurology_Adams. Later, signs of basal ganglionic or cerebellar disease or both are added as discussed later and in Chaps. 17 and 38 but a few cases remain as a pure autonomic failure. In both types of orthostatic hypotension, anhidrosis, erectile dysfunction and atonicity of the bladder may be conjoined, but orthostatic fainting is the main problem.


Neurology_Adams

Neurology_Adams. The clinical differentiation of these two types of orthostatic hypotension depends largely on the appearance, with time, of associated CNS signs as described later. The distinction between the sympathetic postganglionic and the central preganglionic types of disease is also based on pharmacologic and neurophysiologic evidence, but it must be emphasized that the results of these tests do not always conform to clinical expectations from the examination. Nonetheless, Cohen and associates, who studied the postganglionic sudomotor and vasomotor functions of 62 patients with IOH, found that the signs of postganglionic denervation were uncommon in patients classified as having the central type.


Neurology_Adams

Neurology_Adams. In the postganglionic type of autonomic failure, plasma levels of NE are subnormal while the patient is recumbent because of failure of the damaged nerve terminals to synthesize or release catecholamines. When the patient stands, the NE levels do not rise, as they do in a normal person. Also, in this type, there is denervation hypersensitivity to infused NE. In the central preganglionic (Shy-Drager) type, the resting NE levels in the plasma are normal but again, on standing, there is no rise, and the response to exogenously administered NE is normal. In both types, the plasma levels of dopamine b-hydroxylase, the enzyme that converts dopamine to NE, are subnormal (Ziegler et al). The use of these neurochemical tests in clinical practice is difficult and the data in the literature are inconsistent. Low’s monograph should be consulted for procedural details.


Neurology_Adams

Neurology_Adams. Pathologic studies have disclosed the central type of autonomic failure to be somewhat heterogeneous. Oppenheimer, who collected all the reported central cases with complete autopsies, found that they fell into two groups: (1) that which was designated by Adams as striatonigral degeneration or, later, Shy-Drager syndrome, where autonomic failure was associated with a parkinsonian syndrome and often with the presence of cytoplasmic inclusions in sympathetic neurons, and (2) another with involvement of the striatum, cerebellum, pons, and medulla but without inclusions, formerly designated olivopontocerebellar degeneration (there are now reported to be glial and neuronal cytoplasmic inclusions in all these cases). Both conditions are now referred to as multiple system atrophy, the term introduced by Oppenheimer, the first type, MSA-P to denote the parkinsonism and the second type, MSA-C reflecting cerebellar degeneration as discussed in Chap. 38. If the process remains purely an


Neurology_Adams

Neurology_Adams. introduced by Oppenheimer, the first type, MSA-P to denote the parkinsonism and the second type, MSA-C reflecting cerebellar degeneration as discussed in Chap. 38. If the process remains purely an autonomic failure, MSA-A is used.


Neurology_Adams

Neurology_Adams. In all forms of multiple system atrophy, the autonomic failure is attributable to degeneration of lateral horn cells of the thoracic cord. There is also a degeneration of nerve cells in the vagal nuclei as well as nuclei of the tractus solitarius, locus ceruleus, and sacral autonomic nuclei, accounting for laryngeal abductor weakness (laryngeal paralysis and stridor are features in some cases), incontinence, and erectile dysfunction. NE and dopamine are depleted in the hypothalamus (Spokes et al). The sympathetic ganglia have usually been normal. In Parkinson disease, where fainting is sometimes a problem, Lewy bodies are found in degenerating sympathetic ganglion cells but the medications used for treatment also exaggerate hypotension.


Neurology_Adams

Neurology_Adams. Treatment of orthostatic hypotension consists of adequate hydration (at least 1.5 L of fluids per day) with high salt intake, up 8 g of sodium per day, small and frequent meals (to reduce postprandial hypotension) and compression stockings or corset. Fainting can sometimes be avoided by the countermaneuvers of having the patient tightly cross his legs upon standing. Medical treatment can be initiated if nonmedical approaches fail. The peripherally acting alpha agonist, midodrine can be started at 2.5 mg q4h, slowly raising the dose to 5 mg q4h, taking the last dose before about 7 p.m. to void supine hypertension while asleep. The mineralocorticoid fludrocortisone acetate (Florinef) alleviates orthostatic hypotension by volume expansion due to the sodium retention by kidneys. Florinef can be started at dose 0.1 mg daily which may be slowly (over weeks) titrated up 0.9 mg daily. Fludrocortisone may cause hypokalemia and should be used cautiously in patients with severe supine


Neurology_Adams

Neurology_Adams. can be started at dose 0.1 mg daily which may be slowly (over weeks) titrated up 0.9 mg daily. Fludrocortisone may cause hypokalemia and should be used cautiously in patients with severe supine hypertension; its effect may take up to 2 weeks to be manifest so rapid elevation of the dose is not advised. Pyridostigmine stimulates sympathetic ganglia and at doses 30 to 60 mg twice to thrice a day was also reported to be effective in treatment of orthostatic hypotension. Compared to florinef and midodrin, pyridostigmine is less potent pressor but it is much less likely causing supine hypertension. Pyridostigmine also may help to reduce constipation. A newer addition is droxidopa that is a prodrug to the neurotransmitter norepinephrine, acting both centrally and peripherally. Northera is usually started at the dose 100 mg three times a day which can be titrated up to 600 mg three times a day. Northera also increases risk of supine hypertension.


Neurology_Adams

Neurology_Adams. Impairment of autonomic function, of which orthostatic hypotension is the most serious feature, occurs as part of many acute and chronic peripheral neuropathies (e.g., diabetic, alcoholic–nutritional, amyloid, Guillain-Barré, heavy metal, toxic, and porphyric). Disease of the peripheral nervous system may affect the circulation in two ways: the nerves from baroreceptors may be affected, interrupting normal afferent homeostatic reflexes, or postganglionic efferent sympathetic fibers may be involved in their course in the spinal nerves. The severity of the autonomic failure need not parallel the degree of motor weakness. An additional feature of the acute dysautonomias is a tendency to develop hyponatremia, presumably as a result of dysfunction of afferent fibers from venous, right atrial, and aortic arch volume receptors; this elicits a release of antidiuretic hormone arginine vasopressin (AVP). These same stretch baroreceptors are implicated in the intermittent hypertension that


Neurology_Adams

Neurology_Adams. and aortic arch volume receptors; this elicits a release of antidiuretic hormone arginine vasopressin (AVP). These same stretch baroreceptors are implicated in the intermittent hypertension that sometimes complicates these acute neuropathies.


Neurology_Adams

Neurology_Adams. Of particular importance is the autonomic disorder that accompanies diabetic neuropathy. It presents as erectile dysfunction, constipation, or diarrhea (especially at night), hypotonia of the bladder, gastroparesis, and orthostatic hypotension, in some combination. Invariably, there are signs of a sensory polyneuropathy, consisting of a distal loss of vibratory and thermal-pain sensation and reduced or lost ankle reflexes; but again, the severity of affection of the two systems of nerve fibers may not be parallel. The pupils are often small and the amplitude of constriction to light is reduced (similar to Argyll Robertson pupils); this has been attributed to damage of cells in the ciliary ganglia. A curious syndrome or “insulin neuritis” has been described, in which, autonomic failure and painful sensory neuropathy arise at the time of rapid glycemic control (see Gibbons and Freeman, 2010).


Neurology_Adams

Neurology_Adams. Gastroparesis can be disabling, painful, and difficult to treat, for example, in diabetic autonomic neuropathy. Camilleri has reviewed the subject and outlined the defect in gastric emptying that interrelates with glucose metabolism and an unexplained association with psychiatric symptoms. Management is by altering nutritional intake and with metoclopramide for mild cases and additional domperidone, prochlorperazine, and erythromycin in severe ones. Another polyneuropathy with unusually prominent dysautonomia is that caused by amyloidosis. Extensive loss of pain and thermal sensation is usually present; other forms of sensation may also be reduced to a lesser degree. Motor function is much less altered. Sympathetic function is more affected than parasympathetic. Iridoplegia (pupillary paralysis) and disturbances of other smooth muscle and glandular functions are variable. Diabetic and amyloid polyneuropathy are further described in Chap. 46.


Neurology_Adams

Neurology_Adams. Both the primary and secondary types of orthostatic hypotension are also discussed in connection with syncope in Chap. 17. Familial Autonomic Neuropathy in Infants and Children (Riley-Day Syndrome) and Other Inherited Dysautonomias (See Also Chap. 43)


Neurology_Adams

Neurology_Adams. Riley-Day syndrome is a disease of children, inherited as an autosomal recessive trait. The main symptoms are postural hypotension and lability of blood pressure, faulty regulation of temperature, diminished hearing, hyperhidrosis, blotchiness of the skin, insensitivity to pain, emotional lability, and cyclic vomiting. The tendon reflexes are hypoactive, and mild slowing of motor nerve conduction velocities is common. There is denervation sensitivity of the pupils and other structures. The main pathologic feature is a deficiency of neurons in the superior cervical ganglia and in the lateral horns of the spinal cord. Also, according to Aguayo and to Dyck and their colleagues, the number of unmyelinated nerve fibers in the sural nerve is greatly decreased. It is likely that this disease represents a failure of embryologic migration or formation of the firstand second-order sympathetic neurons. It is now known that this defect is the result of a mutation in the gene (IKBKAP) that codes


Neurology_Adams

Neurology_Adams. a failure of embryologic migration or formation of the firstand second-order sympathetic neurons. It is now known that this defect is the result of a mutation in the gene (IKBKAP) that codes for a protein (IKAP) that is currently considered to be associated with transcription regulation (Anderson et al). This results in a decrease in the amount of functional protein in autonomic neurons.


Neurology_Adams

Neurology_Adams. Autonomic symptoms are also a prominent feature of the small-fiber neuropathy of Fabry disease (alpha-galactosidase deficiency) as a result of the accumulation of ceramide in hypothalamic and intermediolateral column neurons (see “Fabry Disease” in Chap. 43). Another inherited form of peripheral dysautonomia is characterized by severe pain in the feet on exercise and an autosomal dominant pattern of inheritance (Robinson et al). Bending, crouching, and kneeling increase stabbing pains in the feet. There is no sweat response to intradermal injection of 1 percent ACh and no autonomic fibers were found in punch biopsies of the skin. Systemic amyloidosis is the other type of peripheral neuropathy that has prominent features of autonomic failure. Autonomic Failure in the Elderly (See Also Chap. 28)


Neurology_Adams

Neurology_Adams. Autonomic Failure in the Elderly (See Also Chap. 28) Orthostatic hypotension, a marker of autonomic sympathetic failure, is defined for research purposes as a reduction of systolic blood pressure of 20 mm Hg or more, or a drop in diastolic blood pressure of 10 mm Hg or more at the third minute of standing. Orthostatic hypotension is typically due to baroreflex failure. In the elderly, orthostatic hypotension commonly results from the use of medications. Neurogenic orthostatic hypotension results from a lesion in autonomic nervous system and is frequently seen in multiple system atrophy, Parkinson’s disease or diabetes.


Neurology_Adams

Neurology_Adams. It should be emphasized how prevalent orthostatic hypotension is in the elderly. Caird and coworkers reported that among individuals who were older than 65 years of age and living at home, 24 percent had a fall of systolic blood pressure on standing of 20 mm Hg; 9 percent had a fall of 30 mm Hg; and 5 percent had a fall of 40 mm Hg. An increased frequency of thermoregulatory impairment also has been documented. The elderly are also more liable to develop hypothermia and, when exposed to high ambient temperature, to hyperthermia. Loss of sweating of the lower parts of the body and increased sweating of the head and arms probably reflect a neuropathy or neuronopathy. The number of sensory ganglion cells decreases with age (de Castro). Erectile dysfunction and incontinence also increase with age, but these, of course, may be the result of a number of processes besides autonomic failure and many of the medications used to treat ailments that come with aging, such as hypertension,


Neurology_Adams

Neurology_Adams. with age, but these, of course, may be the result of a number of processes besides autonomic failure and many of the medications used to treat ailments that come with aging, such as hypertension, prostatic hypertrophy, depression, and impotence, have autonomic effects and can cause orthostatic hypotension.


Neurology_Adams

Neurology_Adams. It is of interest that an idiopathic type of small fiber neuropathy that occurs predominantly in elderly women (“burning hands and feet” syndrome) has no associated autonomic features (see Chap. 43). Horner (Oculosympathetic) and Stellate Ganglion Syndromes (See Also Chap. 13)


Neurology_Adams

Neurology_Adams. Interruption of postganglionic sympathetic fibers at any point along the internal carotid arteries or a lesion of the superior cervical ganglion results in miosis, drooping of the eyelid, and abolition of sweating over one side of the face; this constellation is the Horner, or more properly, Bernard-Horner syndrome (see also “Horner Syndrome” in Chap. 13). The same syndrome in less-obvious form may be caused by interruption of the preganglionic fibers at any point between their origin in the intermediolateral cell column of the C8-T2 spinal segments and the superior cervical ganglion or by interruption of the descending, uncrossed hypothalamospinal pathway in the tegmentum of the brainstem or cervical cord. The common causes are neoplastic or inflammatory involvement of the cervical lymph nodes or proximal part of the brachial plexus, surgical and other types of trauma to cervical structures (e.g., jugular venous catheters), carotid artery dissection, syringomyelic or traumatic


Neurology_Adams

Neurology_Adams. lymph nodes or proximal part of the brachial plexus, surgical and other types of trauma to cervical structures (e.g., jugular venous catheters), carotid artery dissection, syringomyelic or traumatic lesions of the first and second thoracic spinal segments, and infarcts or other lesions of the lateral part of the medulla (Wallenberg syndrome). There is also an idiopathic variety that is in some cases hereditary. If a Horner syndrome develops early in life, the iris on the affected side fails to become pigmented and remains blue or mottled gray-brown (heterochromia iridis; see Fig. 13-10).


Neurology_Adams

Neurology_Adams. A lesion of the stellate ganglion, for example, compression by a tumor arising from the superior sulcus of the lung (Pancoast tumor), produces the interesting combination of a Horner syndrome and paralysis of sympathetic reflexes in the limb (the hand and arm are dry and warm). With preganglionic lesions, facial flushing may develop on the side of the sympathetic disorder; this is brought on in some instances by exercise (harlequin effect). The combination of segmental anhidrosis and an Adie pupil is sometimes referred to as the Ross syndrome; it may be abrupt in onset and idiopathic, or it may follow a viral infection.


Neurology_Adams

Neurology_Adams. Keane has provided data as to the relative frequency of the lesions causing oculosympathetic (Horner) paralysis. In 100 successive cases, 63 were of central type caused by brainstem strokes, 21 were preganglionic from trauma or tumors of the neck, 13 were postganglionic from miscellaneous causes, and in 3 cases the localization could not be determined (see Chap. 13 for further discussion). The pupillary disturbances associated with oculomotor nerve lesions, the Adie pupil, and other parasympathetic and pharmacologic testing for sympathetic abnormalities of pupillary function are considered fully in Chap. 13 and in Table 13-6 with the accompanying text. Apraclonidine, 0.5 percent, has become the favored drug for diagnostic testing as noted earlier.


Neurology_Adams

Neurology_Adams. Lesions of the C4 or C5 segments of the spinal cord, if complete, will interrupt suprasegmental control of both the sympathetic and sacral parasympathetic nervous systems. Much the same effect is observed with lesions of the upper thoracic cord (above T6). Lower thoracic lesions leave much of the descending sympathetic outflow intact, only the descending sacral parasympathetic control being interrupted. Traumatic necrosis of the spinal cord is the usual cause of these states, but they also may be a result of infarction, certain forms of myelitis, radiation damage, and tumors.


Neurology_Adams

Neurology_Adams. As discussed in greater detail in Chap. 42, the initial effect of an acute cervical cord transection is abolition of all sensorimotor reflex, and autonomic functions of the isolated spinal cord. The autonomic changes include hypotension, loss of sweating and piloerection, paralytic ileus and gastric atony, and paralysis of the bladder. The flare component of the axon reflex may be lost. Plasma epinephrine and NE are reduced. This state, known as spinal shock, usually lasts for several weeks as described in Chap. 42. The basic mechanisms are not known, but changes in neurotransmitters (catecholamines, enkephalins, endorphins, substance P, and 5-hydroxytryptamine) and their inhibitory activities are considered to play a role. Naloxone mitigates some of the aspects of spinal shock; this may be, at least in part, the result of release of preformed endogenous opioids from the distal axons that are separated from their cells of origin in the periaqueductal gray region. Once these endogenous


Neurology_Adams

Neurology_Adams. at least in part, the result of release of preformed endogenous opioids from the distal axons that are separated from their cells of origin in the periaqueductal gray region. Once these endogenous substances are exhausted, the phenomenon of spinal shock ends (see Chap. 42).


Neurology_Adams

Neurology_Adams. After spinal shock dissipates, reflex sympathetic and parasympathetic functions return because the afferent and efferent autonomic connections within the isolated segments of the spinal cord are intact, although no longer under the control of higher centers. With cervical cord lesions, there is a loss of the sympathetically mediated cardiovascular changes in response to stimuli reaching the medulla. However, cutaneous stimuli (pinprick or cold) in segments of the body below the transection will raise the blood pressure. However, a fall in blood pressure is not compensated by sympathetic vasoconstriction. Hence tetraplegics are almost obligatorily prone to orthostatic hypotension. Pinching the skin below the lesion causes gooseflesh in adjacent segments. Heating the body results in flushing and sweating over the face and neck, but not in the trunk and legs, because of the loss of connections from the hypothalamus. Bladder and bowel, including their sphincters, which are at first


Neurology_Adams

Neurology_Adams. and sweating over the face and neck, but not in the trunk and legs, because of the loss of connections from the hypothalamus. Bladder and bowel, including their sphincters, which are at first flaccid, become automatic as spinal reflex control returns. There may be reflex penile erection or priapism and even rarely ejaculation. With lesions in the upper thoracic cord, similar but lesser degrees of labile blood pressure are seen; in several of our patients with destructive myelitis, a viral infection of fever brought out episodes of a drop in blood pressure to approximately 80/60 mm Hg and a subsequent rapid rise to 190/110 mm Hg.


Neurology_Adams

Neurology_Adams. After a time, the tetraplegic patient may develop a mass reflex in which flexor spasms of the legs and involuntary emptying of the bladder are associated with a marked rise in blood pressure, bradycardia, and sweating and pilomotor reactions in parts below the cervical segments (autonomic dysreflexia). These reactions may also be evoked by pinprick, passive movement, contactual stimuli of the limbs and abdomen, and pressure on the bladder. An exaggerated vasopressor reaction also occurs in response to injected NE. In such attacks, the patient experiences paresthesias of the neck, shoulders, and arms; tightness in the chest and dyspnea; pupillary dilatation; pallor followed by flushing of the face; sensation of fullness in the head and ears; and a throbbing headache. Plasma NE and dopamine rise slowly during the autonomic discharge. When such an attack is severe and prolonged, electrocardiographic changes may appear, sometimes with evidence of myocardial injury that has been attributed


Neurology_Adams

Neurology_Adams. rise slowly during the autonomic discharge. When such an attack is severe and prolonged, electrocardiographic changes may appear, sometimes with evidence of myocardial injury that has been attributed to direct catecholamine toxicity or, alternatively, to myocardial ischemia caused by increased afterload or to coronary vasospasm. Seizures and visual defects have also been observed, related to cerebral dysautoregulation. Clonidine, up to 0.2 mg tid, has been useful in preventing the hypertensive crises.


Neurology_Adams

Neurology_Adams. Several toxic and pharmacologic agents such as cocaine and phenylpropanolamine are capable of producing abrupt overactivity of the sympathetic and parasympathetic nervous systems—severe hypertension and mydriasis coupled with signs of CNS excitation—sometimes including seizures. Tricyclic antidepressants in excessive doses are also known to produce autonomic effects, but in this case cholinergic blockade leads to dryness of the mouth, flushing, absent sweating, and mydriasis. The main concern with tricyclic antidepressant overdose is the development of a ventricular arrhythmia, also on an autonomic basis, presaged by prolongation of the QT interval on the ECG. Poisoning with organophosphate insecticides (e.g., Parathion), which have anticholinesterase effects, causes a combination of parasympathetic overactivity and motor paralysis (see discussion of poisonings in Chap. 41). A severe autonomic disturbance involving both postganglionic sympathetic and parasympathetic function is


Neurology_Adams

Neurology_Adams. parasympathetic overactivity and motor paralysis (see discussion of poisonings in Chap. 41). A severe autonomic disturbance involving both postganglionic sympathetic and parasympathetic function is produced by ingestion of the rodenticide N-3-pyridylmethyl-N′-p-nitrophenylurea (PNU, Vacor). The exaggerated sympathetic state that accompanies tetanus—manifest by diaphoresis, mydriasis, and labile or sustained hypertension—has been attributed to circulating catecholamines.


Neurology_Adams

Neurology_Adams. Among the most dramatic syndromes of unopposed sympathetic-adrenal medullary hyperactivity occur in cases of severe head injury and with hypertensive cerebral hemorrhage. Three separate mechanisms of the hypersympathetic state are observed at different times after the injury or cerebral hemorrhage: an outpouring of adrenal catecholamines at the time of the ictus with acute hypertension and tachycardia; a brainstem-mediated vasopressor reaction (Cushing response, described in the following pages); and a later chronic phenomenon, consisting of episodes of extreme hypertension, profuse diaphoresis, and pupillary dilatation, usually arising during episodes of several minutes’ duration of rigid extensor posturing (the “diencephalic autonomic seizures” of Penfield, described later and in Chap. 34 in relation to head injury). Most patients who exhibit such paroxysms are decorticate from traumatic lesions of the deep cerebral white matter or from acute hydrocephalus (the likely explanation of


Neurology_Adams

Neurology_Adams. in relation to head injury). Most patients who exhibit such paroxysms are decorticate from traumatic lesions of the deep cerebral white matter or from acute hydrocephalus (the likely explanation of Penfield’s and Jasper’s cases); in any case, they are clearly not epileptic. These attacks may be the result of the removal of inhibitory influences on the hypothalamus, creating, in effect, a hypersensitive decorticated autonomic nervous system.


Neurology_Adams

Neurology_Adams. Regarding the acute sympathetic reaction, experimental evidence suggests that nuclei in the caudal medullary reticular formation (reticularis gigantocellularis and parvocellularis) can precipitate severe hypertensive reactions. These nuclear centers are tonically inhibited by the NTS, which receives afferent input from arterial baroreceptors and chemoreceptors. Bilateral lesions of the NTS therefore produce extreme elevations in blood pressure, and this abrupt rise plays a role in the genesis of “neurogenic” pulmonary edema. These sympathetically mediated effects are eliminated by sectioning of the cervical spinal cord and by alpha-adrenergic blockade.


Neurology_Adams

Neurology_Adams. The Cushing response, reflex, triad, or “reaction,” as Cushing described it, occurs as a result of an abrupt increase in intracranial pressure. It consists of hypertension, bradycardia, and slow, irregular breathing elicited by the stimulation of mechanically sensitive regions in the paramedian caudal medulla (Hoff and Reis). Similar pressure-sensitive areas in the upper cervical spinal cord are also implicated in the Cushing response when intraspinal pressure is raised abruptly; a ventral medullary vasodepressor area that acts in the opposite manner has been found in animals. The proximate cause of the Cushing response is probably from mechanical distortion of the lower brainstem, either from a mass in the posterior fossa or, more often, from a large mass in one of the hemispheres or a subarachnoid hemorrhage that elevates the pressure within the fourth ventricle. Often, only the hypertensive component of the reaction occurs, with the systolic blood pressure reaching levels of 200 mm


Neurology_Adams

Neurology_Adams. hemorrhage that elevates the pressure within the fourth ventricle. Often, only the hypertensive component of the reaction occurs, with the systolic blood pressure reaching levels of 200 mm Hg, spuriously suggesting the presence of a pheochromocytoma or renal artery stenosis. The most severe instances of this type of centrally provoked hypertensive syndrome have occurred in children with cerebellar tumors who presented with headache and extreme systolic hypertension. Difficulty may arise in differentiating this response from hypertensive encephalopathy, especially from cases that derive from renovascular hypertension, which may likewise be accompanied by headache and papilledema. In differentiating these two, it is useful to note that primary hypertensive encephalopathy is associated with a tachycardia or normal heart rate and that systolic blood pressure levels above 210 mm Hg are attained only rarely in the Cushing response.


Neurology_Adams

Neurology_Adams. During episodes of intense sympathetic discharge of any type, there are alterations in the ECG, mainly in the ST segments and T waves; in extreme cases, evidence of myocardial damage can be observed. Both direct sympathetic innervation of the heart and the surge in circulating NE and cortisol are the cause of these findings. A similar hyperadrenergic mechanism has been proposed to explain sudden death from fright, asthma, status epilepticus, and cocaine overdose. Investigations by Schobel and colleagues had suggested that sustained sympathetic overactivity is responsible for the hypertension of preeclampsia, which may be considered in some ways as a dysautonomic state but this may be an oversimplification. Further information on these topics is contained in Chap. 34 and in the reviews by Samuels and Ropper.


Neurology_Adams

Neurology_Adams. A role has also been inferred for the ventrolateral medullary pressor centers in the maintenance of essential hypertension. Geiger and colleagues removed a looped branch of the posteroinferior cerebellar artery that had been apposed to the ventral surface of the medulla in 8 patients who had intractable essential hypertension; they found that 7 improved. Vascular decompression of cranial nerves has proved to be a credible therapeutic measure for hemifacial spasm and some cases of vertigo and trigeminal neuralgia, as discussed in Chap. 4, but the notion of vascular compression of the ventral medulla as a mechanism for typical essential hypertension requires confirmation before being accepted. The Effects of Thoracolumbar Sympathectomy


Neurology_Adams

Neurology_Adams. Surgical resection of the thoracolumbar sympathetic trunk, widely used in the 1940s in the treatment of hypertension but now of historical interest, provided the clinician with the clearest examples of extensive injury to the peripheral sympathetic nervous system, though a similar defect had long been suspected in one type of primary orthostatic hypotension (see earlier). In general, bilateral thoracolumbar sympathectomy results in surprisingly few disturbances. Aside from loss of sweating over the denervated areas of the body, the most pronounced abnormality is an impairment of vasomotor reflexes. In the upright posture, faintness and syncope are frequent because of pooling of blood in the splanchnic bed and lower extremities. Although the blood pressure may fall steadily to shock levels, there is little or no pallor, nausea, vomiting, or sweating—the usual accompaniments of syncope. Bladder, bowel, and sexual function are preserved, though semen is sometimes ejaculated into the


Neurology_Adams

Neurology_Adams. there is little or no pallor, nausea, vomiting, or sweating—the usual accompaniments of syncope. Bladder, bowel, and sexual function are preserved, though semen is sometimes ejaculated into the posterior urethra and bladder (retrograde ejaculation).


Neurology_Adams

Neurology_Adams. This disorder, characterized by episodic, painful blanching of the fingers and presumably caused by digital artery spasm, was first described by Raynaud in 1862. The appearance is of a triphasic sequence of color change of pallor, cyanosis, and subsequent rubor of the affected fingers or toes, but about one-third of such patients have no cyanosis. The episodes are brought on by cold or emotional stress and are usually followed by redness on rewarming. Numbness, paresthesia, and burning often accompany the color changes. It is a disease of early onset, the mean age in idiopathic cases being 14 years; it occurs in a number of clinical settings.


Neurology_Adams

Neurology_Adams. Although most cases are idiopathic, in about half there is an associated connective tissue disease, scleroderma being the main one (Porter et al). In these patients, mostly women with the onset of digital symptoms after age 30 years, the Raynaud phenomenon may antedate the emergence of scleroderma or another rheumatologic autoimmune disorder by many years; such disease usually develops within 2 years. In a small group, predominantly men, the syndrome is induced by local trauma, such as prolonged sculling on a cold day, and particularly by vibratory injury incurred by the sustained use of a pneumatic drill or hammer (a syndrome well known in quarry workers). Obstructive arterial disease—as might occur with the thoracic outlet syndrome, vasospasm because of drugs (ergot, cytotoxic agents, cocaine), previous cold injury (frostbite), and circulating cryoglobulins—is a less-common cause. Still, in 64 of 219 patients studied by Porter and coworkers, the Raynaud syndrome was classified as


Neurology_Adams

Neurology_Adams. cocaine), previous cold injury (frostbite), and circulating cryoglobulins—is a less-common cause. Still, in 64 of 219 patients studied by Porter and coworkers, the Raynaud syndrome was classified as idiopathic, and most of our cases have been of this type. Formerly, the idiopathic form was called Raynaud disease; the type with associated disease is known as Raynaud phenomenon. The presence of distorted and proliferative capillaries in the nail bed, visible with an ophthalmoscope, has been used as a bedside aid to reveal cases of connective tissue disease.


Neurology_Adams

Neurology_Adams. Other processes seen by neurologists, foremost among them carpal tunnel syndrome, also cause cold sensitivity in the fingers. Attacks of digital pain and color change from vasculitis, atherosclerotic vascular occlusion, and other causes of occlusive vascular disease only superficially resemble the Raynaud phenomenon; a search for cryoprecipitable proteins (cryoglobulins) is another cause and a search for these proteins in the blood is appropriate. Irrespective of the associated disease, one of two mechanisms seems to be operative in the pathogenesis—either an arterial constriction or a decrease in the intraluminal pressure. The former, in purest form, is observed in young women on exposure to cold and aggravated by emotional stress; a decrease in intraluminal pressure is associated with arterial obstruction. Treatment is directed to the associated conditions and prevention of precipitating factors. Cervicothoracic sympathectomy has not proved to be an effective measure.


Neurology_Adams

Neurology_Adams. Treatment Avoidance of cold exposure is an obvious strategy, as almost all affected patients have discovered by the time they see the physician. Drugs that cause vasoconstriction are interdicted (ergots, sympathomimetics, clonidine, and serotonin receptor agonists). Calcium channel blockers are most effective, nifedipine being the most widely used, in doses of 30 to 60 mg/d. Other treatments are summarized in the review by Wigley. Erythromelalgia, first described by S. Weir Mitchell, is a condition in which the feet and lower extremities become red and painful on exposure to warm temperatures for prolonged periods (see the section on this disease in Chap. 10, where the clinical and genetic aspects of this illness are described). Disorders of Sweating


Neurology_Adams

Neurology_Adams. Disorders of Sweating Hyperhidrosis results from overactivity of sudomotor nerve fibers under a variety of conditions. It may occur as an initial excitatory phase of certain peripheral neuropathies (e.g., because of arsenic or thallium) and be followed by anhidrosis; it is one aspect of the reflex sympathetic dystrophy pain syndromes (see Chap. 7). This is also observed as a localized effect in painful mononeuropathies (causalgia) and diffusely in a number of painful polyneuropathies (“burning foot” syndrome). A type of nonthermoregulatory hyperhidrosis may occur in spinal paraplegics, as mentioned earlier. Loss of sweating in one part of the body may require a compensatory increase in normal parts—for example, the excessive facial and upper truncal sweating that occurs in patients with transection of the high thoracic cord.


Neurology_Adams

Neurology_Adams. Localized hyperhidrosis may be a troublesome complaint in some patients. One variety, presumably of congenital origin, affects the palms. The social embarrassment of a “succulent hand” or a “dripping paw” is often intolerable. It is taken to be a sign of nervousness, although many persons with this condition disclaim all other anxiety symptoms. Cold, clammy hands are common in individuals with anxiety; indeed, this has been a useful sign in distinguishing an anxiety state from hyperthyroidism, in which the hands are also moist but warm. Extirpation of T2 and T3 sympathetic ganglia relieves the more severe cases of palmar sweating; a Horner syndrome does not develop if the T1 ganglion is left intact. In other cases, the hyperhidrosis affects mainly the feet or the axillae. Treatment with local injections of botulinum toxin has been useful and is now favored over ablative procedures.


Neurology_Adams

Neurology_Adams. Anhidrosis in restricted skin areas is a frequent and useful finding in peripheral nerve disease. It is caused by the interruption of the postganglionic sympathetic fibers, and its boundaries can be mapped by means of the sweat tests described earlier in the chapter. The loss of sweating corresponds to the area of sensory loss. In contrast, sweating is not affected in restricted spinal root disease because there is much intersegmental mixing of the preganglionic axons once they enter the sympathetic chain and there are no preganglionic autonomic fibers in the roots below L3. A postinfectious anhidrosis syndrome has been described, sometimes accompanied by mild orthostatic hypotension. This process is probably a limited form of the “pure pandysautonomia” described earlier. Corticosteroids are said to be beneficial but the process is so infrequent that there are no dependable data.


Neurology_Adams

Neurology_Adams. Other rare but interesting disorders of sweating are Ross syndrome, Adie pupil (see Chap. 13), areflexia and segmental anhidrosis with compensatory hyperhydrosis in other regions of the body, and idiopathic pure sudomotor failure, characterized by urticaria, generalized anhidrosis and elevated IgE; in this syndrome there is no sweating to thermoregulatory needs but preserved sweating with emotional stimuli. Disturbances of Bladder Function With regard to the neurologic diseases that cause bladder dysfunction, multiple sclerosis, usually with urinary urgency, is by far the most common. In Fowler’s clinic, other spinal cord disorders accounted for 12 percent of cases, degenerative diseases (Parkinson disease and multiple system atrophy) for 14 percent, and frontal lobe lesions for 9 percent. These data and the physiologic principles elaborated earlier enable one to understand the effects of the following lesions on bladder function (see Fig. 25-4):


Neurology_Adams

Neurology_Adams. Complete destruction of the cord below T12 This occurs with lesions of the conus, as from trauma, myelodysplasias, tumor, venous angioma, and necrotizing myelitis. The bladder is paralyzed for voluntary and reflex activity and there is no awareness of the state of fullness; voluntary initiation of micturition is impossible; the tonus of the detrusor muscle is abolished and the bladder distends as urine accumulates until there is overflow incontinence; voiding is possible only by the Credé maneuver, that is, lower abdominal compression and abdominal straining. Usually the anal sphincter and colon are similarly affected, and there is “saddle” anesthesia and abolition of the bulbocavernosus and anal reflexes as well as the tendon reflexes in the legs. The cystometrogram shows low pressure and no emptying contractions.