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 : Part 2. Investigation and treatment. Ann Neurol 21:519—529, 1987

When autonomic neuropathy is suspected, noninvasive BLOOD PRESSURE CHANGES. From a study in our tests may be used initially to confirm the diagnosis and laboratory of 76 control subjects aged 5 to 85 years, it to determine whether sympathetic or parasympathetic was concluded that a fall in systolic pressure of greater pathways, or both, are involved. In some cases, further than 30 mm Hg and a fall of diastolic pressure of studies requiring intraarterial catheterization may be greater than 15 mm Hg on standing is abnormal [58], required to localize more precisely the site of the le- although other authors have regarded falls of 20/10 sion in the autonomic nervous system (Table). mm Hg as being outside the normal (control) range [63, 122]. In our own study, and that of others [65], Noninvasive Tests the arterial blood pressure responses to a change in The noninvasive tests of blood pressure and heart rate posture did not alter significantly with age. When response to change in posture, blood pressure re- measuring blood pressure with an inflatable cuff it is sponse to isometric exercise, heart rate variation with important that the arm is extended horizontally when breathing, Valsalva ratio, sweat tests, and plasma the subject is vertical because the hydrostatic effect of noradrenaline levels are adequate screening tests ot the column in the dependent arm may give a falsely sympathetic and parasympathetic function (see Table). elevated blood pressure reading [144]. An abnormal Studies in our laboratory conducted by Ingall [58] fall in arterial blood pressure may occur in patients (which will be reported in detail elsewhere) have who are taking antihypertensive drugs and other medi- shown that abnormal results in two or more of these cations, and in patients with adrenal insufficiency and tests correlate well with abnormalities detected by in- hypovolemia, but if none of these conditions is present vasive tests and indicate autonomic dysfunction. the fall usually signifies the presence of a lesion or lesions in the baroreflex pathways, mainly affecting Blood Pressure and Heart Rate Response vasomotor sympathetic fibers. to Change in Posture The responses of heart rate and blood pressure to CHANGE IN HEART RATE. In resting healthy subjects, changing from the supine to standing position, or to heart rate is determined by the predominantly vagal tilting on a tilt table, are the simplest tests of auto- background autonomic activity [121];,changing from nomic function. the supine to the erect position causes an increase in

From the Department of Neurology, Royal Prince Alfred Hospital, Received July 30, 1986, and in revised form Oct 21. Accepted for and the Department of Medicine, University of Sydney, Sydney, publication Oct 21, 1986. NSW 2006 Australia. Address correspondence to Dr McLeod. 'Part 1, "Disorders of the Autonomic Nervous System: Pathophys- iology and Clinical Features," appeared in the May issue.

519 Clinical Tests of Autonomic Function Test Normal Response Part of Reflex Arc Tested

NONINVASIVE BEDSIDE TESTS Blood-pressure response to standing Fall in BP S30/15 mm Hg Afferent and efferent limbs or vertical tilt Heart rate response to standing Increase 11—29 beats/minute; 30:15 Afferent and efferent limbs ratio SI.04 Isometric exercise Increase in diastolic BP, 15 mm Hg Sympathetic efferent limb Vagal Heart rate variation with respiration Maximum—minimum heart rate =15 afferent and efferent limbs beats/minute; E:I ratio §1.2" Valsalva ratio S1.41 Afferent and efferent limbs Sweat tests Sweating all body and limbs Sympathetic efferent limb Postganglionic sympathetic efferent Axon reflex Local piloerection, sweating fibers Sympathetic Plasma noradrenaline level Rises on tilting from horizontal to efferent limb vertical Rise with induced Plasma vasopressin level hypotension Afferent limb

INVASIVE TESTS Valsalva maneuver Phase I: Rise in BP Afferent and efferent limbs Phase II: Gradual reduction of BP to plateau; tachycardia Phase III: Fall in BP Phase IV: Overshoot of BP, bradycardiaa (1) Slowing of heart rate with induced Baroreflex sensitivity rise of BP* (1) Parasympathetic afferent and effe (2) Steady-state responses to induced rent limbs rise and fall of BP (2) Afferent and efferent limbs

(l)Rise in BP Infusion of pressor drugs (2) Slowing of heart rate (1) Adrenergic receptors (2) Afferent and efferent parasympa- thetic limbs

OTHER TESTS OF VASOMOTOR CONTROL Radiant heating of trunk Increased hand blood flow Sympathetic efferent limb Immersion of hand in hot water Increased blood flow of opposite hand Sympathetic efferent limb Cold pressor test Emotional Reduced blood flow Sympathetic efferent limb stress Inspiratory gasp Increased BP Sympathetic efferent limb Reduced hand blood flow Sympathetic efferent limb

TESTS OF PUPILLARY INNERVATION 4% Cocaine Pupil dilates Sympathetic innervation 0.1% Adrenaline No response Postganglionic sympathetic innervation 1% Hydroxyamphetamine hydro- Pupil dilates Postganglionic sympathetic innervation bromide 2.5% Methacholine, 0.125% pilocar- No response Parasympathetic innervation pine "Age-dependent response. BP = blood pressure; E:I = expiration:inspiration.

520 Annals of Neurology Vol 21 No 6 June 1987 hean rate from 11 to 29 beats a minute [19, 121], but up to age of 40, ratios less than 1.2 may be re- which is independent of age [65]. garded as abnormal. Upon standing, heart rate increases until it reaches a maximum at about the fifteenth heart beat, after which Valsali'a Ratio it slows to a relatively stable rate at about the thirtieth The change in heart rate that occurs in response to a beat. The ratio of the R-R intervals corresponding to brief period of forced expiration against a closed glottis the thirtieth and fifteenth heart beats is known as the or mouthpiece (Valsalva's maneuver) is a useful 30:15 ratio [36], the magnitude of which decreases screening test for abnormalities of autonomic control with increasing age. In young adults, a ratio of less than of the cardiovascular system. During and after Valsal- 1.04 is abnormal. The biphasic heart rate response to va's maneuver, changes occur in cardiac vagal efferent standing is not observed during passive tilting [15] and and sympathetic vasomotor activity that are due to is blocked by atropine; this finding suggests that the stimulation of afferents from baroreceptors in the response is dependent upon normal parasympathetic hean, lungs, aorta, carotid sinuses, and possibly, innervation of the hean [36]. stretch receptors in the lung and muscles of the chest wall [30, 74, 81]. Lesions of any of these autonomic Isometric Exercise pathways or of their central connections are likely to An increase in heart rate, arterial blood pressure, and result in abnormal heart rate responses to Vaisalva's cardiac output occurs during sustained isometric con maneuver. The patient breathes forcefully into a traction of a group of muscles [85]. The cardiovascular mouthpiece attached to a mercury manometer, main- responses are mediated partly by central command taining an expiratory pressure of 40 mm Hg for 10 or [42, 45] and partly by metabolic and/or mechanical 15 seconds while an EKG recording of the hean rate is changes in contracting muscle that activate small fibers made. In normal young subjects, the ratio of the in the afferent limb of the reflex arc [45, 56]. An longest R-R interval to the shonest R-R interval dur- increase in diastolic pressure of less than 15 mm Hg ing the maneuver is at least 1.45 [84]. The response is after 5 minutes of sustained handgrip at 309£ of the age-dependent; a ratio lower than the age-matched maximum voluntary effort is abnormal [37]. The re control values is usually indicative of impaired auto- sponse is not affected by age. In patients with diabetic nomic nervous system control of the heart and blood or uremic neuropathy, the pressor response may be vessels, but low values may also be recorded in pa- reduced or absent [37, 38]. . dents with hean and lung disease.

Hean Rate Variation Tests of Sweating The increase in heart rate that occurs during inspira- In most normal subjects, a rise in body temperature tion (sinus arrhythmia) results from decreased cardiac causes sweating over the entire body, although small vagal activity; it is blocked by atropine but not by pro- areas of anhidrosis are sometimes observed [11, 86]. pranolol [145]. The vagal afferent fibers that are in- The thermal sweat test is usually performed by apply- volved in the reflex innervate pulmonary stretch re- ing radiant heat to the trunk until the oral temperature ceptors [111]. The magnitude of sinus arrhythmia has risen by 1°C. Sweat is detected by one of several decreases with age [134, 146] and is diminished or chemicals that change color when moist [51, 86, 93]. absent in diabetes and other disorders that affect cen- Large areas of anhidrosis are found in patients with tral or peripheral autonomic pathways [78, 80, 113, autonomic neuropathy due to central or peripheral 137, 145]. causes [2, 8, 11, 87, 88, 93, 94, 142]. The pattern of Several tests have been devised for quantitating anhidrosis may be of value in localizing lesions causing heart rate variation [139, 145]. The most reliable Horner's syndrome [105] and peripheral nerve abnor- and simplest to perform are measurements of max- malities [50]. Postganglionic sympathetic lesions caus- imum and minimum heart rate during quiet breathing ing anhidrosis can be distinguished from preganglionic [139, 145]. The patient breathes deeply and steadily at or central lesions by iontophoresis or injection of a 6 breaths per minute, while the electrocardiogram cholinomimetic substance into the skin in the anhi- (EKG) is recorded. Normal subjects have differences drotic area [57, 64, 100]. The sweat response to in heart rate of greater than 15 beats per minute, and cholinomimetics depends upon an axon reflex; it is differences of less than 10 beats per minute are re- reduced or absent with postganglionic sympathetic le- garded as abnormal [99]; however, the response is sions [10] but is unaffected with lesions of the pre- negatively related to age [113, 145]. The expiration- ganglionic or central sympathetic pathways. Several inspiration (E:I) ratio is the ratio of the longest R-R techniques are available for quantitating the sweat interval during expiration to the shortest R-R interval gland responses to iontophoresed or during inspiration [139]; it decreases with age [134], pilocarpine and are useful in detecting diseases such as

Neurological Progress: McLeod and Tuck: Disorders of Autonomic Nervous System: Part 2 521 diabetes mellitus that cause degeneration of postgan- pathways. Plasma vasopressin levels do not increase in glionic sympathetic fibers [66, 67, 90, 91]. healthy subjects after tilting or when applying negative Maneuvers such as a sudden deep breath or electric pressure to the lower body, unless arterial hypotension shock that increase skin sympathetic nerve activity re- is induced [44, 140], In patients with orthostatic hy- sult in transient changes in skin electrical resistance potension due to hypovoiemia or to diseases affecting (psychogalvanic resp.onse) and the potential difference efferent sympathetic pathways only, there is a marked between different areas of skin (electrodermal or skin increase in the plasma vasopressin levels in response to sympathetic response). Both of these phenomena are tilting [140, 148]. By contrast, no rise occurs in pa- abolished when atropkie is iontophoresed, a finding dents with PAF and lesions affecting afferent baro- that suggests they are due to electrochemical changes reflex pathways [118, 148], although an increase in in sweat glands in response to efferent sudomotor the plasma vasopressin level does occur in response sympathetic nerve fiber activity [71, 79]- The latencies to infusions of hypertonic saline [147]. Absence of the of the psychogalvanic and sympathetic skin responses vasopressin response to hypotension in the presence of suggest that they are transmitted by unmyelinated a normal response to an increase in serum osmolality nerve fibers [39]- The sympathetic skin response may may result from lesions affecting baroreceptor afferent be absent in patients with peripheral neuropathies that fibers in the vagus nerves or their central connections involve unmyelinated fibers; it is usually normal in pa- to the paraventricular hypothalamic nuclei [147]. Rest- dents with demyelinadng neuropathies [130]. Patients ing plasma renin levels and the normal increase that who have neuropathies affecting distal sympathetic occurs on standing may be diminished in a variety of nerve fibers may have abnormal skin sympathetic re- autonomic disorders [9, 20, 47, 89]. sponses without significant abnormalities of autonomic The hormone pancreatic polypeptide normally in- control of heart rate and blood pressure [130]. creases in concentration after insulin-induced hypogly- cemia; the response is mediated by cholinergic fibers in Plasma Noradrenaline and Other Biochemical Tests The the vagus nerve [98, 129]. The response is attenuated most useful biochemical test in the clinical investigation or abolished in patients with PAF, PAF with parkinso- of autonomic dysfunction is the measurement of nian features (PAF-P), PAF-MSA, and diabetic auto- noradrenaline levels in plasma. The other tests are nomic neuropathy [76, 98]. more difficult to perform and their value has yet to be clearly established. Plasma noradrenaline content may Invasive and Other Tests be measured at rest in normal subjects; it rises in re- Change in Blood Pressure and Heart Rate sponse to tilting. Patients with progressive autonomic with Valsalva Maneuver failure (PAF) usually have little or no increase in More information about the baroreflex responses to plasma noradrenaline concentrations in response to the Valsalva maneuver can be obtained by the continu- tilting [9, 25, 83, 149]. Patients with" autonomic ous recording of blood pressure and heart rate with an neuropathies affecting postganglionic sympathetic intraarterial catheter (see Table) [9, 63, 131]. The in- vasomotor fibers may have abnormally low plasma creased intrathoracic pressure is transmitted to the noradrenaline levels at rest. The blood pressure rise aorta, causing a transient rise in arterial blood pressure following infusion of pressor drugs such as noradren- (phase I) (Figure). The reduction in venous return to aline may be exaggerated in autonomic disorders. The the heart reduces cardiac output and mean arterial abnormal response may be due to interruption of the blood pressure (phase II), resulting in a tachycardia baroreflex pathways that normally maintain arterial caused by increased cardiac sympathetic activity. When blood pressure within a narrow range and to denerva- the maneuver is stopped, the reduced intrathoracic tion supersensitivity that occurs when postganglionic pressure is recorded as an abrupt fall in the mean arte- sympathetic fibers degenerate [21]. The exaggerated rial pressure (phase III). The increased cardiac output response occurs in patients with lesions of both pre- which accompanies the rise in venous return to the ganglionic and postganglionic sympathetic vasomotor heart, together with the increased peripheral vascular fibers [93, 103, 115]. Tyramine infusions cause an in- resistance due to the increased vasomotor sympathetic crease in arterial blood pressure in normal subjects by activity, causes a marked rise in arterial blood pressure releasing noradrenaline from postganglionic sympa- (phase IV) that is accompanied by a reflex vagally in- thetic nerve fibers [133]. They have been used in an duced bradycardia. The extent of the overshoot of attempt to differentiate preganglionic from postgangli- blood pressure in phase IV decreases with age [49, onic sympathetic nerve damage in PAF and PAF asso- 132]. Clear evidence of an abnormal Valsalva response ciated with multiple-system atrophy (PAF-MSA), but due to impaired circulatory reflexes [63] includes an the results are inconclusive [7, 73, 115]. absence of systolic blood pressure overshoot in phase Measurement of plasma vasopressin levels has been IV, a lower heart rate in phase II than in phase IV, and a used as a test of the afferent limb of the barorerlex fall in mean arterial blood pressure in phase II to 522 Annals of Neurology Vol 21 No 6 June 1987 unloading of low-pressure intrathoracic baroreceptors, which results in increased efferent sympathetic vaso- motor activity.

Baroreflex Sensitivity Graded stimulation of the carotid sinus baroreceptors results in changes in heart rate, , and regional blood flow, all of which may be used as mea- sures 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 relat- ing 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 ele- vated by the intravenous administration of graded doses of phenylephrine or . The baroreflex sensitivity is shown by the slope of the line obtained by (A) Vahalva response in control subject. IB) Valsalra response in plotting each R-R interyaJ-agalnst the systolic pressure patient with primary amyloidosis. Arrows indicate onset and of the preceding pulse [136] ; it is reduced with age cessation of the Vahalva maneuver. Note the pronounced fall in [48]. The technique provides a measure of barore- mean arterial pressure in phase II. absence of bradycardia, and ceptor-mediated vagal activity because it measures absence of overshoot of blood "pressure in phase IV. changes in heart rate in response to relatively rapid increases in arterial blood pressure [75]. Another below 50% of the previous resting mean arterial pres- method of measuring baroreflex sensitivity determines sure. When efferent sympathetic vasoconstrictor activ- the steady-state properties of the baroreflex and there- ity is impaired, there is no overshoot of blood pressure fore assesses the integrated sympathetic and parasym- in phase IV and consequently no bradycardia even if pathetic activity of the heart in response to changes in the baroreceptors, the afferent nerve supply, the vaso- baroreceptor afferent activity [75]. motor center, and the vagus nerves to the heart are intact. If an intraarterial recording is not used to ana- Tests of Peripheral Vasomotor Control Using a variety of lyze the blood pressure changes with Valsalva's maneu- techniques, peripheral blood flow is usually measured ver, it may be impossible to decide whether absence of in the hand, forearm, foot, or leg. An alteration in finger the reflex bradycardia in phase IV is due to impaired blood flow reflects a change in skin circulation, efferent sympathetic vasomotor activity or to abnormal whereas forearm blood flow is mainly a measure of vagal function. An abnormal response may be re- muscle circulation. Changes in skin blood flow may be corded with an intraarterial line when the Valsalva assessed with heat-flow discs [62] or laser Doppler ratio is normal [93}. velocimetry [92]. Muscle blood flow can be measured using venous Lower-Body Negative Pressure occlusion or strain-gauge plethysmography in the The effect of gravity on circulation that follows stand- forearm [23]. However, this method will yield only ing or tilting can be simulated by the application of approximate results because blood flow from both skin negative pressure to the lower body with the subject in and muscle will contribute to the total blood flow in the supine position [9]. In normal subjects, up to 40 the forearm. Other methods of measuring skeletal mm Hg of negative pressure to the lower body causes muscle blood flow include isotope clearance tech- a fall in systolic pressure of less than 10 mm Hg [12], niques [52, 108], measurement of changes in muscle as well as a decrease in forearm and splanchnic blood temperature [13], and measurement of the degree of flow; this phenomenon results from increases in vascu- oxygen desaturation of blood in the deep veins drain- lar resistance [61, 124]. In muscles, sympathetic nerve ing forearm muscles [123]. Such invasive techniques activity and plasma noradrenaline levels are increased are of value in physiological studies, but have a limited when negative pressure is applied to the lower body application in the routine assessment of patients with [44, 138]. These changes are believed to be due to the disordered control ot vasomotor tone.

Neurological Progress: McLeod and Tuck: Disorders of Autonomic Nervous System: Part 2 523 RADIANT HEATING OF TRUNK. The change of blood noradrenaline from postganglionic sympathetic nerve flow to the hand after application of radiant heat to the fibers; absence of midriasis after instillation of 1<% hy- trunk may be measured [24, 68]. A rapid increase in droxyamphetamine hydrobromide solution is indica- the blood flow normally results from vasodiladon ef- tive of a lesion of postganglionic oculosympathetic fected through a reflex pathway above C5 rather than fibers [82] but does not exclude the coexistence of a by a rise in central temperature [3]. more proximal lesion affecting preganglionic or central oculosympathetic fibers. IMMERSION OF HAND IN HOT WATER. Immersing Instillation of 2.5% methacholine or 0.125% pilo- one hand in hot water .causes vasodiladon in the oppo- carpine causes little or no contraction of normally in- site hand as well as an increase in blood flow. This nervated pupils but usually causes miosis in pupils reflex is thought to be due to an elevation in central affected by abnormal parasympathetic innervation [16, temperature [114]. 127]. Marked miosis in response to instillation of di- lute muscarinic agents does not reliably distinguish COLD PRESSOR TEST. The application of ice to the between preganglionic and postganglionic parasyrr.pa- neck or hand elicits a rapid reduction in forearm and thetic lesions. The degree of pupillary constriction in skin blood flow and an increase in arterial blood pres- response to 2.5% methacholine is similar in patients sure in most normal subjects [53, 59, 92]. The re- with Adie's syndrome (postganglionic lesion) and in sponse is believed to be a reflex mediated through those with oculomotor nerve damage affecting pre- afferent pain and temperature fibers from the skin and ganglionic fibers [117]. efferent sympathetic vasoconstrictor fibers [59].

EMOTIONAL STRESS. Emotional stress (mental arith- Summary of Tests of Autonomic Function metic, a sudden loud noise, painful or emotional The noninvasive tests of heart rate response to breath- stimuli) causes a transient increase in the sympathetic ing and change in posture assess vagal function primar- vasomotor nerve activity in normal subjects that can be ily; the change in blood pressure on standing, response recorded directly using microneurography [30] or in- of blood pressure on isometric exercise, the sweat test, directly by measuring the accompanying decrease in and plasma noradrenaline levels mainly evaluate sym- blood flow in the skin or extremities [31] or the in- pathetic efferent function. These investigations pro- crease in arterial blood pressure [97]. These tests are vide very adequate screening for autonomic dysfunc- used to evaluate the sympathetic efferent activity be- tion. It should be emphasized that responses to most cause they do not involve activation of the afferent of these tests are age-dependent, and every laboratory limb of the reflex arc. Unfortunately, the tests cannot should establish its own control values over a wide age be completely relied on to indicate autonomic dysfunc- range. Studies in our laboratory have shown that ab- tion; some normal persons may also have no response normal findings in two or more of these noninvasive [63]. tests correlate well with abnormalities detected by tests using arterial catheterization. The invasive tests of au- INSPIRATORY GASP. A sudden inspiratory gasp tonomic function and the special tests of vasomotor causes a reduction of blood flow through the hand. control and pupillary innervation are usually necessary The reflex is present in patients with cervical cord le- only in doubtful cases or for research purposes. sions above the sympathetic outflow to the hand, and hence the pathway passes mainly through the spinal Treatment of Autonomic Failure cord [43]. Treatment of autonomic failure has been discussed in several recent reviews [5, 18, 110, 125, 141]. A funda- Tests of Pupillary Innervation mental principle when considering treatment is that, Abnormal autonomic innervation of the pupil may be if there is an underlying treatable cause for the auto- associated with a variety of autonomic neuropathies nomic dysfunction (for example, acute inflammatory (Table) [69, 135]. Instillation of 4% cocaine into the neuropathy, diabetes, or toxins), the appropriate ther- conjunctival sac causes pupillary dilation when the apy should be administered. sympathetic innervation is intact. The response is re- One of the most troublesome manifestations of au- duced or absent when there is a lesion in the ocu- tonomic disorders is orthostatic hypotension. Treat- losympathetic pathways [82]. Instillation of 0.1% ment is usually not required unless the patient experi- adrenaline into the conjunctival sac has no effect on ences symptoms. Drug therapy is aimed at increasing the normal pupil but causes dilation in the pupil whose the blood volume or vasomotor tone or both, but it is postganglionic sympathetic innervation is interrupted difficult and unreliable because control of orthostatic as a result of denervation supersensitivity. Hydroxy- hypotension is frequently complicated by supine hy- amphetamine causes pupillary dilation by releasing pertension.

524 Annals of Neurology Vol21 No 6 June 1987