Disorders of the Autonomic Nervous System: Part 2. Investigation and Treatment*

Transcription

1 NEUROLOGICAL PROGRESS Disorders of the Autonomic Nervous System: Part 2. Investigation and Treatment* J. G. McLeod, PPhil, FRACP, and R. R. Tuck, PhD, FRACP Autonomic function may be adequately tested with noninvasive tests of sympathetic and parasympathetic pathways, including: the response of blood pressure to change in posture and isometric contraction, heart rate response to standing, variation in heart rate with respiration, Valsalva ratio, sweat tests, and plasma noradrenaline measurements. Abnormal results in two or more of these tests indicate autonomic dysfunction. Intraarterial catheterization and tests of vasomotor function are usually required only in doubtful cases or for research purposes. Treatment of autonomic dysfunction is focused primarily on bladder control and control of orthostatic hypotension. Orthostatic hypotension is best treated with physical measures, pharmacologically with 9-alpha-fluorohydrocortisone and dihydroergotamine mesylate. A number of other agents may be tried but results have been less effective. McLeod JG, Tuck RR: Disorders of the autonomic nervous system: Part 2. Investigation and treatment. Ann Neurol 21: , 1987 When autonomic neuropathy is suspected, noninvasive tests may be used initially to confirm the diagnosis and to determine whether sympathetic or parasympathetic pathways, or both, are involved. In some cases, further studies requiring intraarterial catheterization may be required to localize more precisely the site of the lesion in the autonomic nervous system (Table). Noninvasive Tests The noninvasive tests of blood pressure and heart rate response to change in posture, blood pressure response to isometric exercise, heart rate variation with breathing, Valsalva ratio, sweat tests, and plasma noradrenaline levels are adequate screening tests ot sympathetic and parasympathetic function (see Table). Studies in our laboratory conducted by Ingall [58] (which will be reported in detail elsewhere) have shown that abnormal results in two or more of these tests correlate well with abnormalities detected by invasive tests and indicate autonomic dysfunction. Blood Pressure and Heart Rate Response to Change in Posture The responses of heart rate and blood pressure to changing from the supine to standing position, or to tilting on a tilt table, are the simplest tests of autonomic function. BLOOD PRESSURE CHANGES. From a study in our laboratory of 76 control subjects aged 5 to 85 years, it was concluded that a fall in systolic pressure of greater than 30 mm Hg and a fall of diastolic pressure of greater than 15 mm Hg on standing is abnormal [58], although other authors have regarded falls of 20/10 mm Hg as being outside the normal (control) range [63, 122]. In our own study, and that of others [65], the arterial blood pressure responses to a change in posture did not alter significantly with age. When measuring blood pressure with an inflatable cuff it is important that the arm is extended horizontally when the subject is vertical because the hydrostatic effect of the column in the dependent arm may give a falsely elevated blood pressure reading [144]. An abnormal fall in arterial blood pressure may occur in patients who are taking antihypertensive drugs and other medications, and in patients with adrenal insufficiency and hypovolemia, but if none of these conditions is present the fall usually signifies the presence of a lesion or lesions in the baroreflex pathways, mainly affecting vasomotor sympathetic fibers. CHANGE IN HEART RATE. In resting healthy subjects, heart rate is determined by the predominantly vagal background autonomic activity [121];,changing from the supine to the erect position causes an increase in From the Department of Neurology, Royal Prince Alfred Hospital, and the Department of Medicine, University of Sydney, Sydney, NSW 2006 Australia. Received July 30, 1986, and in revised form Oct 21. Accepted for publication Oct 21, Address correspondence to Dr McLeod. 'Part 1, "Disorders of the Autonomic Nervous System: Pathophysiology and Clinical Features," appeared in the May issue. 519

2 Clinical Tests of Autonomic Function Test Normal Response Part of Reflex Arc Tested NONINVASIVE BEDSIDE TESTS Blood-pressure response to standing or vertical tilt Heart rate response to standing Isometric exercise Heart rate variation with respiration Valsalva ratio Sweat tests Axon reflex Plasma noradrenaline level Plasma vasopressin level INVASIVE TESTS Valsalva maneuver Baroreflex sensitivity Infusion of pressor drugs OTHER TESTS OF VASOMOTOR CONTROL Radiant heating of trunk Immersion of hand in hot water Cold pressor test Emotional stress Inspiratory gasp TESTS OF PUPILLARY INNERVATION Fall in BP S30/15 mm Hg Increase beats/minute; 30:15 ratio SI.04 Increase in diastolic BP, 15 mm Hg Maximum minimum heart rate =15 beats/minute; E:I ratio 1.2" S1.4 1 Sweating all body and limbs Local piloerection, sweating Rises on tilting from horizontal to vertical Rise with induced hypotension Phase I: Phase II: Rise in BP Gradual reduction of BP to plateau; tachycardia Phase III: Fall in BP Phase IV: Overshoot of BP, bradycardia a (1) Slowing of heart rate with induced rise of BP* (2) Steady-state responses to induced rise and fall of BP (l)rise in BP (2) Slowing of heart rate Increased hand blood flow Increased blood flow of opposite hand Reduced blood flow Increased BP Reduced hand blood flow Vagal afferent and efferent limbs Postganglionic sympathetic efferent fibers Sympathetic efferent limb Afferent limb (1) Parasympathetic afferent and effe rent limbs (2) (1) Adrenergic receptors (2) Afferent and efferent parasympathetic limbs 4% Cocaine Pupil dilates 0.1% Adrenaline No response 1% Hydroxyamphetamine hydro- Pupil dilates bromide 2.5% Methacholine, 0.125% pilocar- No response pine "Age-dependent response. BP = blood pressure; E:I = expiration:inspiration. Sympathetic innervation Postganglionic sympathetic innervation Postganglionic sympathetic innervation Parasympathetic innervation 520 Annals of Neurology Vol 21 No 6 June 1987

3 hean rate from 11 to 29 beats a minute [19, 121], which is independent of age [65]. Upon standing, heart rate increases until it reaches a maximum at about the fifteenth heart beat, after which it slows to a relatively stable rate at about the thirtieth beat. The ratio of the R-R intervals corresponding to the thirtieth and fifteenth heart beats is known as the 30:15 ratio [36], the magnitude of which decreases with increasing age. In young adults, a ratio of less than 1.04 is abnormal. The biphasic heart rate response to standing is not observed during passive tilting [15] and is blocked by atropine; this finding suggests that the response is dependent upon normal parasympathetic innervation of the hean [36]. Isometric Exercise An increase in heart rate, arterial blood pressure, and cardiac output occurs during sustained isometric con traction of a group of muscles [85]. The cardiovascular responses are mediated partly by central command [42, 45] and partly by metabolic and/or mechanical changes in contracting muscle that activate small fibers in the afferent limb of the reflex arc [45, 56]. An increase in diastolic pressure of less than 15 mm Hg after 5 minutes of sustained handgrip at 309 of the maximum voluntary effort is abnormal [37]. The re sponse is not affected by age. In patients with diabetic or uremic neuropathy, the pressor response may be reduced or absent [37, 38].. Hean Rate Variation The increase in heart rate that occurs during inspiration (sinus arrhythmia) results from decreased cardiac vagal activity; it is blocked by atropine but not by propranolol [145]. The vagal afferent fibers that are involved in the reflex innervate pulmonary stretch receptors [111]. The magnitude of sinus arrhythmia decreases with age [134, 146] and is diminished or absent in diabetes and other disorders that affect central or peripheral autonomic pathways [78, 80, 113, 137, 145]. Several tests have been devised for quantitating heart rate variation [139, 145]. The most reliable and simplest to perform are measurements of maximum and minimum heart rate during quiet breathing [139, 145]. The patient breathes deeply and steadily at 6 breaths per minute, while the electrocardiogram (EKG) is recorded. Normal subjects have differences in heart rate of greater than 15 beats per minute, and differences of less than 10 beats per minute are regarded as abnormal [99]; however, the response is negatively related to age [113, 145]. The expirationinspiration (E:I) ratio is the ratio of the longest R-R interval during expiration to the shortest R-R interval during inspiration [139]; it decreases with age [134], but up to age of 40, ratios less than 1.2 may be regarded as abnormal. Valsali'a Ratio The change in heart rate that occurs in response to a brief period of forced expiration against a closed glottis or mouthpiece (Valsalva's maneuver) is a useful screening test for abnormalities of autonomic control of the cardiovascular system. During and after Valsalva's maneuver, changes occur in cardiac vagal efferent and sympathetic vasomotor activity that are due to stimulation of afferents from baroreceptors in the hean, lungs, aorta, carotid sinuses, and possibly, stretch receptors in the lung and muscles of the chest wall [30, 74, 81]. Lesions of any of these autonomic pathways or of their central connections are likely to result in abnormal heart rate responses to Vaisalva's maneuver. The patient breathes forcefully into a mouthpiece attached to a mercury manometer, maintaining an expiratory pressure of 40 mm Hg for 10 or 15 seconds while an EKG recording of the hean rate is made. In normal young subjects, the ratio of the longest R-R interval to the shonest R-R interval during the maneuver is at least 1.45 [84]. The response is age-dependent; a ratio lower than the age-matched control values is usually indicative of impaired autonomic nervous system control of the heart and blood vessels, but low values may also be recorded in padents with hean and lung disease. Tests of Sweating In most normal subjects, a rise in body temperature causes sweating over the entire body, although small areas of anhidrosis are sometimes observed [11, 86]. The thermal sweat test is usually performed by applying radiant heat to the trunk until the oral temperature has risen by 1 C. Sweat is detected by one of several chemicals that change color when moist [51, 86, 93]. Large areas of anhidrosis are found in patients with autonomic neuropathy due to central or peripheral causes [2, 8, 11, 87, 88, 93, 94, 142]. The pattern of anhidrosis may be of value in localizing lesions causing Horner's syndrome [105] and peripheral nerve abnormalities [50]. Postganglionic sympathetic lesions causing anhidrosis can be distinguished from preganglionic or central lesions by iontophoresis or injection of a cholinomimetic substance into the skin in the anhidrotic area [57, 64, 100]. The sweat response to cholinomimetics depends upon an axon reflex; it is reduced or absent with postganglionic sympathetic lesions [10] but is unaffected with lesions of the preganglionic or central sympathetic pathways. Several techniques are available for quantitating the sweat gland responses to iontophoresed acetylcholine or pilocarpine and are useful in detecting diseases such as Neurological Progress: McLeod and Tuck: Disorders of Autonomic Nervous System: Part 2 521

4 diabetes mellitus that cause degeneration of postganglionic sympathetic fibers [66, 67, 90, 91]. Maneuvers such as a sudden deep breath or electric shock that increase skin sympathetic nerve activity result in transient changes in skin electrical resistance (psychogalvanic resp.onse) and the potential difference between different areas of skin (electrodermal or skin sympathetic response). Both of these phenomena are abolished when atropkie is iontophoresed, a finding that suggests they are due to electrochemical changes in sweat glands in response to efferent sudomotor sympathetic nerve fiber activity [71, 79]- The latencies of the psychogalvanic and sympathetic skin responses suggest that they are transmitted by unmyelinated nerve fibers [39]- The sympathetic skin response may be absent in patients with peripheral neuropathies that involve unmyelinated fibers; it is usually normal in padents with demyelinadng neuropathies [130]. Patients who have neuropathies affecting distal sympathetic nerve fibers may have abnormal skin sympathetic responses without significant abnormalities of autonomic control of heart rate and blood pressure [130]. Plasma Noradrenaline and Other Biochemical Tests The most useful biochemical test in the clinical investigation of autonomic dysfunction is the measurement of noradrenaline levels in plasma. The other tests are more difficult to perform and their value has yet to be clearly established. Plasma noradrenaline content may be measured at rest in normal subjects; it rises in response to tilting. Patients with progressive autonomic failure (PAF) usually have little or no increase in plasma noradrenaline concentrations in response to tilting [9, 25, 83, 149]. Patients with" autonomic neuropathies affecting postganglionic sympathetic vasomotor fibers may have abnormally low plasma noradrenaline levels at rest. The blood pressure rise following infusion of pressor drugs such as noradrenaline may be exaggerated in autonomic disorders. The abnormal response may be due to interruption of the baroreflex pathways that normally maintain arterial blood pressure within a narrow range and to denervation supersensitivity that occurs when postganglionic sympathetic fibers degenerate [21]. The exaggerated response occurs in patients with lesions of both preganglionic and postganglionic sympathetic vasomotor fibers [93, 103, 115]. Tyramine infusions cause an increase in arterial blood pressure in normal subjects by releasing noradrenaline from postganglionic sympathetic nerve fibers [133]. They have been used in an attempt to differentiate preganglionic from postganglionic sympathetic nerve damage in PAF and PAF associated with multiple-system atrophy (PAF-MSA), but the results are inconclusive [7, 73, 115]. Measurement of plasma vasopressin levels has been used as a test of the afferent limb of the barorerlex 522 Annals of Neurology Vol 21 No 6 June 1987 pathways. Plasma vasopressin levels do not increase in healthy subjects after tilting or when applying negative pressure to the lower body, unless arterial hypotension is induced [44, 140], In patients with orthostatic hypotension due to hypovoiemia or to diseases affecting efferent sympathetic pathways only, there is a marked increase in the plasma vasopressin levels in response to tilting [140, 148]. By contrast, no rise occurs in padents with PAF and lesions affecting afferent baroreflex pathways [118, 148], although an increase in the plasma vasopressin level does occur in response to infusions of hypertonic saline [147]. Absence of the vasopressin response to hypotension in the presence of a normal response to an increase in serum osmolality may result from lesions affecting baroreceptor afferent fibers in the vagus nerves or their central connections to the paraventricular hypothalamic nuclei [147]. Resting plasma renin levels and the normal increase that occurs on standing may be diminished in a variety of autonomic disorders [9, 20, 47, 89]. The hormone pancreatic polypeptide normally increases in concentration after insulin-induced hypoglycemia; the response is mediated by cholinergic fibers in the vagus nerve [98, 129]. The response is attenuated or abolished in patients with PAF, PAF with parkinsonian features (PAF-P), PAF-MSA, and diabetic autonomic neuropathy [76, 98]. Invasive and Other Tests Change in Blood Pressure and Heart Rate with Valsalva Maneuver More information about the baroreflex responses to the Valsalva maneuver can be obtained by the continuous recording of blood pressure and heart rate with an intraarterial catheter (see Table) [9, 63, 131]. The increased intrathoracic pressure is transmitted to the aorta, causing a transient rise in arterial blood pressure (phase I) (Figure). The reduction in venous return to the heart reduces cardiac output and mean arterial blood pressure (phase II), resulting in a tachycardia caused by increased cardiac sympathetic activity. When the maneuver is stopped, the reduced intrathoracic pressure is recorded as an abrupt fall in the mean arterial pressure (phase III). The increased cardiac output which accompanies the rise in venous return to the heart, together with the increased peripheral vascular resistance due to the increased vasomotor sympathetic activity, causes a marked rise in arterial blood pressure (phase IV) that is accompanied by a reflex vagally induced bradycardia. The extent of the overshoot of blood pressure in phase IV decreases with age [49, 132]. Clear evidence of an abnormal Valsalva response due to impaired circulatory reflexes [63] includes an absence of systolic blood pressure overshoot in phase IV, a lower heart rate in phase II than in phase IV, and a fall in mean arterial blood pressure in phase II to

5 unloading of low-pressure intrathoracic baroreceptors, which results in increased efferent sympathetic vasomotor activity. (A) Vahalva response in control subject. IB) Valsalra response in patient with primary amyloidosis. Arrows indicate onset and cessation of the Vahalva maneuver. Note the pronounced fall in mean arterial pressure in phase II. absence of bradycardia, and absence of overshoot of blood "pressure in phase IV. below 50% of the previous resting mean arterial pressure. When efferent sympathetic vasoconstrictor activity is impaired, there is no overshoot of blood pressure in phase IV and consequently no bradycardia even if the baroreceptors, the afferent nerve supply, the vasomotor center, and the vagus nerves to the heart are intact. If an intraarterial recording is not used to analyze the blood pressure changes with Valsalva's maneuver, it may be impossible to decide whether absence of the reflex bradycardia in phase IV is due to impaired efferent sympathetic vasomotor activity or to abnormal vagal function. An abnormal response may be recorded with an intraarterial line when the Valsalva ratio is normal [93}. Lower-Body Negative Pressure The effect of gravity on circulation that follows standing or tilting can be simulated by the application of negative pressure to the lower body with the subject in the supine position [9]. In normal subjects, up to 40 mm Hg of negative pressure to the lower body causes a fall in systolic pressure of less than 10 mm Hg [12], as well as a decrease in forearm and splanchnic blood flow; this phenomenon results from increases in vascular resistance [61, 124]. In muscles, sympathetic nerve activity and plasma noradrenaline levels are increased when negative pressure is applied to the lower body [44, 138]. These changes are believed to be due to the Baroreflex Sensitivity Graded stimulation of the carotid sinus baroreceptors results in changes in heart rate, vascular resistance, and regional blood flow, all of which may be used as measures of baroreflex sensitivity [70]. Carotid sinus pres - sure can be varied by applying controlled suction to a chamber applied to the neck [35]. The technique has been used to study the relationship between changes of carotid sinus pressure and arterial blood pressure, heart rate, and blood flow in the forearm [1, 33, 34, 40, 96]. Baroreflex sensitivity may also be measured by relating the changes in the R-R interval to changes in blood pressure induced by pharmacological agents that have no direct effect on heart rate. Blood pressure is elevated by the intravenous administration of graded doses of phenylephrine or angiotensin. The baroreflex sensitivity is shown by the slope of the line obtained by plotting each R-R interyaj-agalnst the systolic pressure of the preceding pulse [136] ; it is reduced with age [48]. The technique provides a measure of baroreceptor-mediated vagal activity because it measures changes in heart rate in response to relatively rapid increases in arterial blood pressure [75]. Another method of measuring baroreflex sensitivity determines the steady-state properties of the baroreflex and therefore assesses the integrated sympathetic and parasympathetic activity of the heart in response to changes in baroreceptor afferent activity [75]. Tests of Peripheral Vasomotor Control Using a variety of techniques, peripheral blood flow is usually measured in the hand, forearm, foot, or leg. An alteration in finger blood flow reflects a change in skin circulation, whereas forearm blood flow is mainly a measure of muscle circulation. Changes in skin blood flow may be assessed with heat-flow discs [62] or laser Doppler velocimetry [92]. Muscle blood flow can be measured using venous occlusion or strain-gauge plethysmography in the forearm [23]. However, this method will yield only approximate results because blood flow from both skin and muscle will contribute to the total blood flow in the forearm. Other methods of measuring skeletal muscle blood flow include isotope clearance techniques [52, 108], measurement of changes in muscle temperature [13], and measurement of the degree of oxygen desaturation of blood in the deep veins draining forearm muscles [123]. Such invasive techniques are of value in physiological studies, but have a limited application in the routine assessment of patients with disordered control ot vasomotor tone. Neurological Progress: McLeod and Tuck: Disorders of Autonomic Nervous System: Part 2 523

6 RADIANT HEATING OF TRUNK. The change of blood flow to the hand after application of radiant heat to the trunk may be measured [24, 68]. A rapid increase in the blood flow normally results from vasodiladon effected through a reflex pathway above C5 rather than by a rise in central temperature [3]. IMMERSION OF HAND IN HOT WATER. Immersing one hand in hot water.causes vasodiladon in the opposite hand as well as an increase in blood flow. This reflex is thought to be due to an elevation in central temperature [114]. COLD PRESSOR TEST. The application of ice to the neck or hand elicits a rapid reduction in forearm and skin blood flow and an increase in arterial blood pressure in most normal subjects [53, 59, 92]. The response is believed to be a reflex mediated through afferent pain and temperature fibers from the skin and efferent sympathetic vasoconstrictor fibers [59]. EMOTIONAL STRESS. Emotional stress (mental arithmetic, a sudden loud noise, painful or emotional stimuli) causes a transient increase in the sympathetic vasomotor nerve activity in normal subjects that can be recorded directly using microneurography [30] or indirectly by measuring the accompanying decrease in blood flow in the skin or extremities [31] or the increase in arterial blood pressure [97]. These tests are used to evaluate the sympathetic efferent activity because they do not involve activation of the afferent limb of the reflex arc. Unfortunately, the tests cannot be completely relied on to indicate autonomic dysfunction; some normal persons may also have no response [63]. INSPIRATORY GASP. A sudden inspiratory gasp causes a reduction of blood flow through the hand. The reflex is present in patients with cervical cord lesions above the sympathetic outflow to the hand, and hence the pathway passes mainly through the spinal cord [43]. Tests of Pupillary Innervation Abnormal autonomic innervation of the pupil may be associated with a variety of autonomic neuropathies (Table) [69, 135]. Instillation of 4% cocaine into the conjunctival sac causes pupillary dilation when the sympathetic innervation is intact. The response is reduced or absent when there is a lesion in the oculosympathetic pathways [82]. Instillation of 0.1% adrenaline into the conjunctival sac has no effect on the normal pupil but causes dilation in the pupil whose postganglionic sympathetic innervation is interrupted as a result of denervation supersensitivity. Hydroxyamphetamine causes pupillary dilation by releasing noradrenaline from postganglionic sympathetic nerve fibers; absence of midriasis after instillation of 1<% hydroxyamphetamine hydrobromide solution is indicative of a lesion of postganglionic oculosympathetic fibers [82] but does not exclude the coexistence of a more proximal lesion affecting preganglionic or central oculosympathetic fibers. Instillation of 2.5% methacholine or 0.125% pilocarpine causes little or no contraction of normally innervated pupils but usually causes miosis in pupils affected by abnormal parasympathetic innervation [16, 127]. Marked miosis in response to instillation of dilute muscarinic agents does not reliably distinguish between preganglionic and postganglionic parasyrr.pathetic lesions. The degree of pupillary constriction in response to 2.5% methacholine is similar in patients with Adie's syndrome (postganglionic lesion) and in those with oculomotor nerve damage affecting preganglionic fibers [117]. Summary of Tests of Autonomic Function The noninvasive tests of heart rate response to breathing and change in posture assess vagal function primarily; the change in blood pressure on standing, response of blood pressure on isometric exercise, the sweat test, and plasma noradrenaline levels mainly evaluate sympathetic efferent function. These investigations provide very adequate screening for autonomic dysfunction. It should be emphasized that responses to most of these tests are age-dependent, and every laboratory should establish its own control values over a wide age range. Studies in our laboratory have shown that abnormal findings in two or more of these noninvasive tests correlate well with abnormalities detected by tests using arterial catheterization. The invasive tests of autonomic function and the special tests of vasomotor control and pupillary innervation are usually necessary only in doubtful cases or for research purposes. Treatment of Autonomic Failure Treatment of autonomic failure has been discussed in several recent reviews [5, 18, 110, 125, 141]. A fundamental principle when considering treatment is that, if there is an underlying treatable cause for the autonomic dysfunction (for example, acute inflammatory neuropathy, diabetes, or toxins), the appropriate therapy should be administered. One of the most troublesome manifestations of autonomic disorders is orthostatic hypotension. Treatment is usually not required unless the patient experiences symptoms. Drug therapy is aimed at increasing the blood volume or vasomotor tone or both, but it is difficult and unreliable because control of orthostatic hypotension is frequently complicated by supine hypertension. 524 Annals of Neurology Vol21 No 6 June 1987